蛋白激酶抑制剂的设计合成及其抗癌活性研究
|
摘要
人蛋白激酶由500多个激酶组成，负责磷酸化底物蛋白的丝氨酸残基、苏氨残基或酪氨酸残基，调控细胞内的各种信号传导过程。蛋白激酶活性异常已被证明与多种疾病相关，如癌症、免疫系统疾病、神经退行性疾病以及炎症、类风湿性关节炎、牛皮癣、糖尿病和动脉粥样硬化等。因此，蛋白激酶抑制剂特别是选择性的蛋白激酶抑制剂具有很大的新药开发潜力。
鉴于许多天然的吲哚咔唑类类化合物，如staurosporine、K252a和Granulatimide，属于ATP-竞争性抑制剂，它们都是非选择性的蛋白激酶抑制剂。在此，本论文结合基于结构的药物分子设计方法，通过点击化学，构建了一个新的分子骨架，以模拟天然的吲哚咔唑化合物。
在最初的概念证明阶段，本论文合成了23个新化合物，其中我们发现了一个苗头化合物，该化合物在1mM浓度水平上表现出很强的肿瘤细胞抑制活性。为寻找该化合物的靶标蛋白，筛选了124个激酶，该化合物表现出极高的选择性，在500nM浓度时仅对其中四个激酶表现出明显的抑制活性。此外，我们测定了该化合物对这四个激酶的半抑制浓度并通过ATP-竞争性实验证实了该化合物是ATP-竞争性激酶抑制剂。最后，我们对其中四个化合物与GSK3-β结晶蛋白的对接进行了研究，获得了与实验数据一致的计算结果。
在苗头化合物的基础长，我们用二唑片段替代三唑片段，合成了3个吡唑马来酰亚胺衍生物和3个咪唑马来酰亚胺衍生物。MTT结果显示，吡唑马来酰亚胺衍生物的肿瘤细胞抑制活性有所降低，而咪唑马来酰亚胺衍生物的肿瘤细胞抑制活性比苗头化合物提高了一个数量级。
StaN氧化酶在staurosporine的生物合成途径中，负责第二个糖苷键的生成，为了研究StaN氧化酶的底物适应性，我们通过14步化学反应制备了一个StaN底物分子。
The more than500human protein kinases constitute a large family of enzymescatalyzing phosphorylation of Ser, Thr or Tyr residues in substrate proteins, andthese kinases are responsible for the control of a wide variety of signal transductionprocesses within the cell. Deregulated protein kinase activity has been implicated ina panel of diseases, including cancer, disorders of the immune system,neurodegenerative disorders, and etc. Selective protein kinase inhibitors are thereforeof great potentials in new drug development.
Given that many natural indolocarbazole compounds, including staurosporine,K252a, Granulatimide, and etc, are ATP-competitive kinse inhibitor, it is of nosurprise that these natural indolocabazoles are typically non-selective kintaseinhibitors. Herein, we present the recent progress on our kinase inhibitor projectwhich created a new molecular scaffold to mimic the natural indolocarbazoles viathe application of click chemistry.
Totally23new compounds were prepared at the initial proof-of-concept stage.Among them, one hit compound was discovered which showed potent growthinhibition of activity against tumor cell lines at1mΜ concentration level. In aone-dose-124-kinases-screening assay, this compound surprisingly showed greatselectivity. Only4members of these124kinases were remarkably prohibited by thiscompound at500nM. The IC50values of these4kinases were determined. And theATP-competition experiment confirmed this compound as an ATP competitiveinhibitor. Docking studies of some of these compounds to GSK-3β crystal structurewere performed, and consistent computational results to the assay date wereobtained.
The triazole fragment was also replaced by pyrazole and iminazole fragment,3new compounds contained pyrazole fragment and3new compounds containediminazole fragment were prepared. The results of the MTT showed that the pyrazolecompounds were less active than the triazole compounds, while the inhibition activity of iminazole compounds against tumor cell was one magnitude more potentthan the hit compound.
In order to study the substrate adaptability of the StaN which was responsiblefor the building of the second glycosidic linkage in the biosynthesis of staurosporine,we also prepared one substrate of the StaN through14steps.
鉴于许多天然的吲哚咔唑类类化合物，如staurosporine、K252a和Granulatimide，属于ATP-竞争性抑制剂，它们都是非选择性的蛋白激酶抑制剂。在此，本论文结合基于结构的药物分子设计方法，通过点击化学，构建了一个新的分子骨架，以模拟天然的吲哚咔唑化合物。
在最初的概念证明阶段，本论文合成了23个新化合物，其中我们发现了一个苗头化合物，该化合物在1mM浓度水平上表现出很强的肿瘤细胞抑制活性。为寻找该化合物的靶标蛋白，筛选了124个激酶，该化合物表现出极高的选择性，在500nM浓度时仅对其中四个激酶表现出明显的抑制活性。此外，我们测定了该化合物对这四个激酶的半抑制浓度并通过ATP-竞争性实验证实了该化合物是ATP-竞争性激酶抑制剂。最后，我们对其中四个化合物与GSK3-β结晶蛋白的对接进行了研究，获得了与实验数据一致的计算结果。
在苗头化合物的基础长，我们用二唑片段替代三唑片段，合成了3个吡唑马来酰亚胺衍生物和3个咪唑马来酰亚胺衍生物。MTT结果显示，吡唑马来酰亚胺衍生物的肿瘤细胞抑制活性有所降低，而咪唑马来酰亚胺衍生物的肿瘤细胞抑制活性比苗头化合物提高了一个数量级。
StaN氧化酶在staurosporine的生物合成途径中，负责第二个糖苷键的生成，为了研究StaN氧化酶的底物适应性，我们通过14步化学反应制备了一个StaN底物分子。
The more than500human protein kinases constitute a large family of enzymescatalyzing phosphorylation of Ser, Thr or Tyr residues in substrate proteins, andthese kinases are responsible for the control of a wide variety of signal transductionprocesses within the cell. Deregulated protein kinase activity has been implicated ina panel of diseases, including cancer, disorders of the immune system,neurodegenerative disorders, and etc. Selective protein kinase inhibitors are thereforeof great potentials in new drug development.
Given that many natural indolocarbazole compounds, including staurosporine,K252a, Granulatimide, and etc, are ATP-competitive kinse inhibitor, it is of nosurprise that these natural indolocabazoles are typically non-selective kintaseinhibitors. Herein, we present the recent progress on our kinase inhibitor projectwhich created a new molecular scaffold to mimic the natural indolocarbazoles viathe application of click chemistry.
Totally23new compounds were prepared at the initial proof-of-concept stage.Among them, one hit compound was discovered which showed potent growthinhibition of activity against tumor cell lines at1mΜ concentration level. In aone-dose-124-kinases-screening assay, this compound surprisingly showed greatselectivity. Only4members of these124kinases were remarkably prohibited by thiscompound at500nM. The IC50values of these4kinases were determined. And theATP-competition experiment confirmed this compound as an ATP competitiveinhibitor. Docking studies of some of these compounds to GSK-3β crystal structurewere performed, and consistent computational results to the assay date wereobtained.
The triazole fragment was also replaced by pyrazole and iminazole fragment,3new compounds contained pyrazole fragment and3new compounds containediminazole fragment were prepared. The results of the MTT showed that the pyrazolecompounds were less active than the triazole compounds, while the inhibition activity of iminazole compounds against tumor cell was one magnitude more potentthan the hit compound.
In order to study the substrate adaptability of the StaN which was responsiblefor the building of the second glycosidic linkage in the biosynthesis of staurosporine,we also prepared one substrate of the StaN through14steps.
引文
[1] Nishzuka Y: Intracellular signaling by hydrolysis of phospholipid and activation of proteinkinase C. Science1992,258:607–614.
[2] Edelman A, Blumenthal D, Krebs E: Protein serine/threonine kinases. Annu Rev Biochem1987,56:567–613.
[3] Fantl W, Johnson, D, Williams LT: Signaling by receptor tyrosine kinases. Annu RevBiochem1993,62:453–481.
[4] Yarden Y, Ulrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem1988,57:443–478.
[5] Manning G, Whyte DB, Martinez R, et al.: The protein kinase complement of the humangenome. Science,2002,298:1912–1234.
[6] Cohen P: The role of protein phosphorylation in human health and disease. Eur J Biochem2001,268:5001–5010.
[7] G. Burnett, and E. P. Kennedy, The enzymatic phosphorylation of proteins. J Biol Chem1954,211:969–980.
[8] Uckun F, Mao C: Tyrosine kinases as new molecular targets in treatment of inflammatorydisorders and leukemia. Curr Pharm Des,2004,10:1083–1091.
[9] Knuutila S, Bjorkqvist AM, Autio K, Tarkkaqnen M, Wolf M, Monni O, et al.: DNA copynumber amplifications in human neoplasms: review of comparative genomic hybridizationstudies. Am J Pathol,1998,152:1107–1123.
[10] Noble M, Endicott J, Johnson L: Protein kinase inhibitors: insights into drug design fromstructure. Science,2004,303:1800–1805.
[11] Dancy J, Sausville EA: Issues and progress with protein kinase inhibitors for cancertreatment. Nat Rev Drug Discov,2003,2:296–313.
[12] DiGiovanna MP, Stern DF, Edgerton SM, et al.: Relationship of epidermal growth factorreceptor expression to ErbB-2signaling activity and prognosis in breast cancer patients. JClin Oncol,2005,23:1152–1160.
[13] Piccart-Gebhart M, Procter M, Leyland-Jones B, et al.: Herceptin Adjuvant (HERA) TrialStudy Team. N Engl J Med,2005,353:1659-1672.
[14] Druker B, Tamura S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosinekinase on the growth of Bcr-Abl positive cells. Nat Med,1996,2:561–566.
[15] Druker B, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of theBCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med,2001,344:1031–1037.
[16] Barker AJ, Gibson KH, Grundy W, et al.: Studies leading to the identification of ZD1839(IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinaseinhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett,2001,11:1911–1914.
[17] Karaman M, Herrgard S, Treiber D, et al.: A quantitative analysis of kinase inhibitorselectivity. Nat Biotechnol,2008,26:127–132.
[18] Druker BJ: STI571(Gleevec) as a paradigm for cancer therapy. Trends Mol Med,2002,8(Suppl): S14–S18.
[19] Sawyer T: Novel oncogenic protein kinase inhibitors for cancer therapy. Curr Med ChemAnti-Cancer Agents,2004,4:449–455.
[20] E Ter Haar, WP Walters, S Pazhanisamy, P Taslimi, AC Pierce, GW Bemis, et al.: Kinasechemogenomics: targeting the human kinome for target validation and drug discovery. MiniRev Med Chem,2004,4:235–253.
[21] Nagar B, Bornmann WG, Pellicena P, et al.: Crystal structures of the kinase domain of c-Ablin complex with the small molecule inhibitors PD173955and imatinib (STI-571). CancerRes,2002,62:4236–4243.
[22] Corbin A, La Rosee P, Stoffregen E, et al.: Several Bcr-Abl kinase domain mutantsassociated with imatinib mesylate resistance remain sensitive to imatinib. Blood,2003,10:4611–4614.
[23] Gorre M, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571cancer therapycaused by BCR-ABL gene mutation or amplification. Science,2001,293:876–880.
[24] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651–661.
[25] Walker E, Pacold M, Perisic O, et al.: Structural determinants of phosphoinositide3-kinaseinhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell,2000,6:909–919.
[26] Tong L, Pav S, White D, Rogers S, et al.: A highly specific inhibitor of human p38MAPkinase binds in the ATP pocket. Nat Struct Biol,1997,4:311–316.
[27] Fitzgerald C, Patel S, Becker J, et al.: Structural basis for p38alpha MAP kinasequinazolinone and pyridol-pyrimi-dine inhibitor specificity. Nat Struct Biol,2003,10:764–769.
[28] Shen G: Selective protein kinase C inhibitors and their applications. Curr Drug TargetsCardiovasc Haematol Disord,2003,3:301–307.
[29] Kim C, Xuong NH, Taylor SS: Crystal structure of a complex between the catalytic andregulatory (RIalpha) subunits of PKA. Science,2005,307:690–696.
[30] Karin M, Yamamoto Y, Wang Q: The IKK NF-kappa B system: a treasure trove for drugdevelopment. Nat Rev Drug Discov,2004,3:17–26.
[31] May M, Ghosh S: IκB kinases: kinsmen with different crafts. Science,1999,284:271-273.
[32] Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronicinflammatory diseases. N Engl J Med,1997,336:1066–1071.
[33] Haefner B: NF-kappa B: arresting a major culprit in cancer. Drug Discov Today,2002,7:653–663.
[34] Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol,2002,3:221–227.
[35] May M, D’Acquisto F, Madge L, et al.: Selective inhibition of NFkB activation by a peptidethat blocks the interaction of NEMO with the IkB kinase complex. Science,2000,289:1550–1554.
[36] Pallàs M, Verdaguer E, Jordà EG, et al.: Flavopiridol: an antitumor drug with potentialapplication in the treatment of neurodegenerative diseases. Med Hypoth,2005,64:120–123.
[37] Knockaert M, Greengard P, Meijer L: Pharmacological inhibitors of cyclin-dependentkinases. Trends Pharmacol Sci,2002,23:417–425.
[38] Pavletich NP: Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, theircyclin activators, and Cip and INK4inhibitors. J Mol Biol,1999,287:821–828.
[39] Stevenson LM, Deal MS, Hagopian JC, et al.: Activation mechanism of CDK2: role ofcyclin binding versus phosphorylation. Biochemistry,2002,41:8528-8534.
[40] Hirai H, Kawanishi N, Iwasawa Y: Recent advances in the development of selective smallmolecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem,2005,5:167–179.
[41] Jeffrey P, Tong L, Pavletich N: Structural basis of inhibition of CDK-cyclin complexes byINK4inhibitors. Genes Dev,2000,14:3115–3125.
[42] Roy KK, Sausville E: Early development of cyclin dependent kinase modulators. CurrPharm Des,2001,7:1669–1687.
[43] Parry D, Bates S, Mann DJ, et al.: Lack of cyclin D-Cdk complexes in Rb-negative cellscorrelates with high levels of p16INK4/MTS1tumour suppressor gene product. EMBO J,1995,14:503–511.
[44] Hall M, Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdkinhibitors in human cancer. Adv Cancer Res,1996,68:67–108.
[45] Zuo L, Weger J, Yang Q, et al.: Germline mutations in the p16INK4a binding domain ofCDK4in familial melanoma. Nat Genet,1996,12:97–99.
[46] Ghosh S, Liu X, Zheng Y, et al.: Rational design of potent and selective EGFR tyrosinekinase inhibitors as anticancer agents. Curr Cancer Drug Targets,2001,1:129–140.
[47] Wehrman TS, Raab WJ, Casipit CL, et al.: A system for quantifying dynamic proteininteractions defines a role for Herceptin in modulating ErbB2interactions. Proc Natl AcadSci US,2006,103:19063–19068.
[48] Schlessinger J, Ullrich A: Growth factor signaling by receptor tyrosine kinases. Neuron1992,9:383–391.
[49] Zhu H, Iaria J, Orchard S, et al.: Epidermal growth factor receptor: association ofextracellular domain negatively regulates intracellular kinase activation in the absence ofligand. Growth Factors,2003,21:15–30.
[50] Boldt S, Kolch W: Targeting MAPK signalling: Prometheus’ fire or Pandora’s box? CurrPharm Des,2004,10:1885–1905.
[51] Kumar S, Boehm J, Lee J: p38MAP kinases: key signalling molecules as therapeutic targetsfor inflammatory diseases. Nat Rev Drug Discov,2003,2:717–726.
[52] Sebolt-Leopold J, Herrera R: Targeting the mitogen-activated protein kinase cascade to treatcancer. Nat Rev Cancer,2004,4:937–947.
[53] Pearson G, Robinson F, Beers Gibson T, et al.: Mitogen-activated protein (MAP) kinasepathways: regulation and physiological functions. Endocr Rev,2001,22:153–183.
[54] Marshall C: How do small GTPase signal transduction pathways regulate cell cycle entry?Curr Opin Cell Biol,1999,11:732–736.
[55] McMahon M, Woods D: Regulation of the p53pathway by Ras, the plot thickens. BiochimBiophys Acta,2001,1471: M63–M71.
[56] Gupta S, Barrett T, Whitmarsh AJ, et al.: Selective interaction of JNK protein kinaseisoforms with transcription factors. EMBO J,1996,15:2760–2770.
[57] Manning A, Davis R: Targeting JNK for therapeutic benefit: from junk to gold? Nat DrugDiscov,2003,2:554–565.
[58] Manning AM, Mercurio F: Transcription inhibitors in inflammation. Expert Opin InvestigDrugs,1997,6:555–567.
[59] Bennett BL, Sasaki DT, Murray BW, et al.: SP600125, an anthrapyrazolone inhibitor of JunN-terminal kinase. Proc Natl Acad Sci USA,2001,98:13681–13686.
[60] Han Z, Boyle DL, Chang L, et al.: c-Jun N-terminal kinase is required for metalloproteinaseexpression and joint destruction in inflammatory arthritis. J Clin Invest,2001,108:73–81.
[61] Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulinresistance. Nature,2002,420:333–336.
[62] Adams JL, Badger AM, Kumar S, et al: p38MAP kinase: molecular target for the inhibitionof pro-inflammatory cytokines. Prog Med Chem,2001,38:1–60.
[63] Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov2003,2:473–488.
[64] Badger AM, Bradbeer J, Votta B, et al: Pharmacological profile of SB203580, a selectiveinhibitor of cytokine suppressive binding protein/p38kinase, in animal models of arthritis,bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther,1996,279:1453–1461.
[65] Regan J, Breitfelder S, Cirillo P, et al.: Pyrazole urea-based inhibitors of p38MAP kinase:from lead compound to clinical candidate. J Med Chem,2002,45:2994–3008.
[66] Badger AM, Griswold DE, Kapadia R, et al.: Disease-modifying activity of SB242235, aselective inhibitor of p38mitogen-activated protein kinase, in rat adjuvant-induced arthritis.Arthritis Rheum,2000,43:175–183.
[67] Mclay LM, Halley F, Souness JE, et al.: The discovery of RPR200765A, a p38MAP kinaseinhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem,2001,9:537–554.
[68] Ma XL, Kumar S, Gao F, et al.: Inhibition of p38mitogen-activated protein kinase decreasescardiomyocyte apoptosis and improves cardiac function after myocardial ischemia andreperfusion. Circulation,1999,99:1685–1691.
[69] Gutkind JS: The pathways connecting G protein coupled receptors to the nucleus throughdivergent MAPK’s. J Biol Chem,1998,273:1839–1842.
[70] Wen D, Nong Y, Morgan JG, et al.: A selective small molecule IkappaB Kinase betainhibitor blocks nuclear factor kappaB-mediated inflammatory responses in humanfibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther,2006,317:989–1001.
[71] Palanki MS, Gayo-Fun L, Shevlin G, et al.: Structure-activity relationship studies of ethyl2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate:an inhibitor of AP-1and NF-kappaB mediated gene expression. Bioorg Med Chem Lett,2002,12:2573–2577.
[72] Castro AC, Dang L, Soucy F, et al.: Novel IKK inhibitors: beta-carbolines. Bioorg MedChem Lett,2003,13:2419–2422.
[73] Burke JR, Pattoli MA, Gregor KR, al.: BMS-345541is a highly selective inhibitor of Ikappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappaB-dependent transcription in mice. J Biol Chem,2003,278:1450–1456.
[74] Bhat R, Budd S, Haeberlein L, et al: Glycogen synthase kinase3: a drug target for CNStherapies. J Neurochem,2004,89:1313–1317.
[75] Murphy E: Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest,2004,113:1526–1528.
[76] Coghlan MP, Culbert AA, Cross DA, et al.: Selective small molecule inhibitors of glycogensynthase kinase-3modulate glycogen metabolism and gene transcription. Chem Biol,2000,7:793–803.
[77] Mussmann R, Geese M, Harder F, et al.: Inhibition of GSK3promotes replication andsurvival of pancreatic beta cells. J Biol Chem,2007,282:12030-12037.
[78] Lucas J, Hernandez F, Gomez-Ramos P, et al.: Decreased nuclear beta-catenin, tauhyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.EMBO J,2001,20:27-39.
[79] Rondinone CM: Diabetes: the latest developments in inhibitors, insulin sensitisers, new drugtargets and novel approaches. October18-19,2004, The Hatton, London, UK. Expert OpinTher Targets,2005,9,415-418.
[80] Leal EC, Santiago AR, Ambrósio AF: Old and new drug targets in diabetic retinopathy:from biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNSNeurol Disord,2005,4:421–434.
[81] Beckman JA, Goldfine AB, Gordon MB, et al.: Inhibition of protein kinase Cbeta preventsimpaired endothelium-dependent vasodilation caused by hyperglycemia in humans. CircRes,2002,90:107–111.
[82] Meier M, King GL: Protein kinase C activation and its pharmacological inhibition invascular disease. Vasc Med,2000,5:173–185.
[83] Frank RN: Potential new medical therapies for diabetic retinopathy: protein kinase Cinhibitors. Am J Ophthalmol,2002,133:693–698.
[84] Kunkel MW, Hook KE, Howard CT, et al.: Inhibition of the epidermal growth factorreceptor tyrosine kinase by PD153035in human A431tumors in athymic nude mice. InvestNew Drug,1996,13:295-302.
[85] Woodburn JR, Barker AJ, Gibson KH, et al.: ZD1839, an epidermal growth factor tyrosinekinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res,1997,38:633-634.
[86] Zimmermann J, Buchdunger E, Mett H, et al.: Potent and selective inhibitors of the Ablkinase-phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett,1997,7:187-192.
[87] Zimmermann J, Buchdunger E, Mett H, et al.: Phenylamino-pyrimidine (PAP)-derivatives: anew class of potent and highly selective PDGF-receptor autophosphorylation inhibitors.Bioorg Med Chem Lett,1996,6:1221-1226.
[88] Zimmermann J, Caravatti G, Mett H, et al.: a new class of potent and selective inhibitors ofprotein kinase C. Arch Pharm Weinheim,1996,329:371-376.
[89] Thomas AP, inventor. Zeneca WO-09515952;1995.
[90] Davis PD, Moffat DFC, Davis JM, et al. Celltech Therapeutics WO-09719065;1997.
[91] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519774;1995.
[92] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519970;1995.
[93] Thompson AM, Bridges AJ, Fry DW, et al.: Tyrosine kinase inhibitors.7.7-amino-4-(phenylamino)-and7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines:a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factorreceptor. J Med Chem,1995,38:3780-3788.
[94] Rewcastle GF, Palmer BD, Thompson AM, et al.: Tyrosine kinase inhibitors.10. Isomeric4-[(3-bromophenyl)amino]pyrido[d]pyrimidines are potent ATP binding site inhibitors ofthe tyrosine kinase function of the epidermal growth factor receptor. J Med Chem,1996,39:1823-1835.
[95] Rewcastle GW, Murray DK, Elliott WL, et al.: Tyrosine kinase inhibitors.14.Structure-activity relationships for methyl-amino-substituted derivatives of4-[(3-bromophenyl)amino]-6(methylamino)-pyrido[3,4-d]pyr-imidine (PD158780), apotent and speci c inhibitor of the tyrosine kinase activity of receptors for the EGF familyof growth factor. J Med Chem,1998,41:742-751.
[96] Thompson AM, Murray DK, Elliott WL, et al.: J Med Chem,1997,40:3915-3925.
[97] Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA. J MedChem1997;40:1519.
[98] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802438;1998.
[99] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802437;1998.
[100] Cockerill GS, Guntrip SB, McKeown SK, et al., inventors. Glaxo Group WO-09713771;1997.
[101] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-19629652-A1;1998.
[102] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-1960831-A1;1997.
[103] Blankley CJ, Boschelli DH, Doherty AM, et al. Warner Lambert WO-09634867;1996.
[104] Connolly CJC, Hamby JM, Schroeder MC, et al.: Discovery and structure-activity studiesof a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. Bioorg Med ChemLett,1997,7:2415-2418.
[105] Hamby JM, Connolly CJ, Schroeder MC, et al.: Structure-activity relationships for a novelseries of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem,1997,40:2296-2303.
[106] Mohammadi M, Froum S, Hamby JM, et al.: Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain. EMBO J,1998,17:5896-5904.
[107] Panek RL, Lu GH, Klutchko SR, et al.: a new nanomolar potent and broadly active proteinkinase inhibitor. J Pharmacol Exp Ther,1997,283:1433-1444.
[108] Boschelli DH, Wu Z, Klutchko SR, et al.: synthesis and tyrosine kinase inhibitory activityof a series of2-amino-8H-pyrido[2,3-d]pyrimidines: identigication of potent, selectiveplatelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem,1998,41:4365-4377.
[109] Rewcastle GF, Bridges AJ, Fry DW, et al.: Tyrosine Kinase Inhibitors.12. Synthesis andStructure-Activity Relationships for6-Substituted4-(Phenylamino) pyrimido[5,4-d]pyrimidines Designed as Inhibitors of the Epidermal Growth Factor Receptor. J MedChem,1997,40:1820-1826.
[110] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae WO-09732880;1997.
[111] Himmelsbach F, Dahmann G, von Ruden T, et al. WO-09732882;1997.
[112] Traxler P, Bold G, Buchdunger E, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[113] Missbach M, Jeschke M, Field JB, et al.: A novel inhibitor of the tyrosine kinase Srcsuppresses phosphorylation of its major cellular substrates and reduces bone resorption invitro and in rodent models in vivo. Bone,1999,24:437-449.
[114] Missbach M, Green J, Susa M, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[115] Altmann E, inventor. Novartis AG WO-09734895;1997.
[116] Altmann E, Missbach M, Widler L. Novartis AG WO-09732879;1997.
[117] Altmann E, Missbach M, Widler L, et al. Novartis AG WO-09749706;1997.
[118] Altmann E, Widler L, Missbach M. Novartis AG WO-09728161;1997.
[119] Missbach M. Ciba–Geigy WO-09610028;1996.
[120] Henry JR, Rupert KC, Dodd JH, et al.:6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (RWJ68354): A Potent and Selective p38KinaseInhibitor J Med Chem,1998,41:4196-4198.
[121] Hanke JH, Gardner JP, Dow RL, et al.: Discovery of a novel, potent, and Srcfamily-selective tyrosine kinase Inhibitor: study of Lck-and FynT-dependent T cellactivation. J Biol Chem,1996,271:695-701.
[122] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651-661.
[123] Bishop AC, Kung CY, Shah K, et al.: Generation of monospecific nanomolar tyrosinekinase inhibitors via a chemical genetic approach. J Am Chem Soc,1999,121:627-631.
[124] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814451;1998.
[125] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814449;1998.
[126] Tang PC, Sun L, McMahon G, et al. Sugen WO-09850356;1998.
[127] Tang C, Sun L, McMahon G, et al. Sugen WO-09807695;1998.
[128] Sun L, Tran F, App H, et al.: Synthesis and biological evaluations of3-substitutedindolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity towardparticular receptor tyrosine kinases. J Med Chem,1998,41:2588-2603.
[129] Battistini C, Ermoli A, Vioglio S, et al. Pharmacia&Upjohn WO-09745409;1997.
[130] Battistini C, Vioglio S, Buzzetti F, et al. Pharmacia&Upjohn WO-09746551;1997.
[131] McNutt RW, Jung DK, Harris PA, et al., inventors. Glaxo Group WO-09910325;1999.
[132] Lackey K, Chapman D, Crosby RM, et al. Proc Am Assoc Cancer Res1999;40:124.
[133] Davis ST, Dickerson SH, Frye SV, et al. Glaxo Group WO-09915500;1999.
[134] Luzzio MJ, Bramson N, Dickerson S, et al. Proc Am Assoc Cancer Res,1999,40:622.
[135] Parker CW, Entsch B, Letham DS. Inhibitors of cytokinin metabolism I. Inhibition of twoenzymes which metabo-lize cytokinins. Phytochem,1986,25:303-310.
[136] Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol,1996,6:393-397.
[137] Vesely J, Havlicek L, Strnad M, et al. Progress in Cell Cycle Research. Eur J Biochem1994,224:771-786.
[138] MacCallum DE, Melville J, Frame S, et al.: Seliciclib (CYC202, R-Roscovitine) inducescell death in multi-ple myeloma cells by inhibition of RNA polymerase II-dependenttranscription and down-regulation of Mcl-1Cancer Research,2005,65(12):5399–5407.
[139] Noopur Raje, Shaji Kumar, Teru Hideshima, et al.: Seliciclib (CYC202or R-roscovitine), asmall-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulationofMcl-1in multiple myeloma. Blood,2005,106(3):1042–1047.
[140] Rossi AG, Sawatzky DA, Walker A, et al.: Cyclin-dependent kinase inhibitors enhance theresolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine,2006,12(9):1056–1064.
[141] Gray NS, Wodicka L, Thunnissen AMWH, et al.: Exploiting chemical libraries, structure,and genomics in the search for kinase inhibitors. Science,1998,281:533-538.
[142] Imbach P, Capraro HG, Furet P, et al.:2,6,9-trisubstituted purines: optimization towardshighly potent and selective CDK1inhibitors. Bioorg Med Chem Lett,1999,9:91-96.
[143] Adams JL, Boehm JC, Kassis S, et al.: Pyrimidinylimidazole inhibitors of CSBP/p38kinase demonstrating decreased inhibition of hepatic cytochrome P450enzymes. BioorgMed Chem Lett,1998,8:3111-3116.
[144] Jackson JR, Bolognese B, Hillegass L, et al.: Pharmacological Effects of SB220025, aSelective Inhibitor of P38Mitogen-Activated Protein Kinase, in Angiogenesis and ChronicInflammatory Disease Models. J Pharmacol Exp Ther,1998,284:687-692.
[145] Frantz B, Klatt T, Pang M, et al.: Induction of apoptosis by SB202190through inhibitionof p38β mitogen-activated protein kinase. Biochem,1998,37:13846-13853.
[146] Liverton NJ, Butcher JW, Clairbone CF, et al.: Design and Synthesis of Potent, Selective,and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38Mitogen-ActivatedProtein Kinase. J Med Chem,1999,42:2180-2190.
[147] Heimbrook DC, Huber HE, Stirdivant SM, et al.: Epidermal growth factor induction of thec-jun promoter by a Rac pathway. Proc Am Assoc Cancer Res,1998,39:558-559.
[148] Meyer T, Regenass U, Fabbro D, et al.: A derivative of staurosporine (CGP41251) showsselectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivoanti-tumor activity. Int J Cancer,1989,43:85-856.
[149] Mehta AB, Virchis AE, Jones DT, et al.: The formation of new blood vessels from anexisting vascular network. Blood,1997,90:3634-3641.
[150] P. A. Campochiaro and the C99-PKC412-003Study Group, Invest. Ophthalmol. VisualSci.,2004,45:922–931.
[151] Takahashi I, Kobayashi E, Asano K, et al. UCN-01, a selective inhibitor of protein kinaseC from Streptomyces. J Antibiot,1987,40:1782-1784.
[152] Akinaga S, Sugiyama K, Akiyama T. UCN-01(7-hydroxystaurosporine) and otherindolocarbazole compounds: a new generation of anti-cancer agents for the new century?.Anti-Cancer Drug Des,2000,15:43–52.
[153] K. Grosios, UCN-01Kyowa Hakko Kogyo Co. Curr. Opin. Invest. Drugs (Thomson Sci.),2001,2:287–297.
[154] Senderowicz AM. The Cell Cycle as a Target for Cancer Therapy: Basic and ClinicalFindings with the Small Molecule Inhibitors Flavopiridol and UCN-01. Oncologist,2002,7(suppl.3),12–19.
[155] Butler MS. Natural products to drugs: natural product derived compounds in clinical trials.Nat. Prod. Rep.,2005,22:162–195.
[156] ClinicalTrials.gov (a service of the US National Institutes of Health). Available athttp://clinicaltrials.gov.
[157] Fuse E, Kuwabara T, Sparreboom A, et al.: Review of UCN-01development: a lesson inthe importance of clinical pharmacology. J. Clin. Pharmacol,2005,45:394–403.
[158] Sausville EA. Indifferently Pursued or Unowned Drugs: Who Should Lead WhereCompanies Do Not Tread?. J. Clin. Oncol,2005,23:1796–1798.
[159] Camoratto AM, Jani J P, Angeles TS, et al.: CEP-751inhibits trk receptor tyrosine kinaseactivity in vitro and exhibits anti-tumor activity. Int. J. Cancer,1997,72:673–679.
[160] Ruggeri BA, Miknyoczki SJ, Singh J, et al.: Role of neurotrophin–trk interactions inoncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors inpre-clinical tumor models. Curr. Med. Chem.,1999,6:845–857.
[161] Strock CJ, Park JI, Rosen DM, et al.: Activity of irinotecan and the tyrosine kinaseinhibitor CEP-751in medullary thyroid cancer. J Clin Endocrinol Metab. J. Clin.Endocrinol. Metab.,2006,91:79–84.
[162] Strock CJ, Park JI, Rosen M, et al.: Activated RET Tyrosine Kinase Activity and BlockMedullary Thyroid Carcinoma Cell Growth. Cancer Res.,2003,63:5559–5563.
[163] Brown P, Levis M, McIntyre E, et al.: Constitutively activated FLT3phosphorylates BADpartially through pim-1. Leukemia,2006,20:1368–1376.
[164] Smith BD, Levis M, Beran M, et al.: Single Agent CEP-701, a novel FLT3inhibitor, showsbiologic response and clinical activity in patients with relapsed or refractory acute myeloidleukemia. Blood,2004,103:3669–3676.
[165] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solidtumors. Invest. New Drugs,2004,22:449–458.
[166] Camoratto AM, Jani JP, Angeles T, Maroney A, et al.: CEP-751inhibits trk receptortyrosine kinase activity in vitro and exhibits anti-tumor activity. Int J Cancer,1997,72:673-679.
[167] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solidtumors. Invest. New Drugs,2004,22:449–458.
[168] Gingrich DE, Reddy DR, Iqbal MA, et al.: A New Class of Potent Vascular EndothelialGrowth Factor Receptor Tyrosine Kinase Inhibitors: Structure Activity Relationships fora Series of9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo [3,4-c]carbazole-5-ones and the Identification of CEP-5214and Its Dimethylglycine Ester Prodrug ClinicalCandidate CEP-7055. J. Med. Chem.,2003,46:5375–5388.
[169] Jirousek MR, Gillig JR, Gonzalez CM, et al.:(S)-13-[(Dimethylamino)methyl]-10,11,14,15–tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues: Isozyme SelectiveInhibitors of Protein Kinase Cβ. J. Med. Chem.,1996,39:2664–2671.
[170] Tuttle KR, Bakris GL, Toto RD, et al.: The Effect of Ruboxistaurin on Nephropathy inType2Diabetes. Diabetes Care,2005,28:2686–2690.
[171] Vinik AI, Bril V, Kempler P, et al.: Treatment of symptomatic diabetic peripheralneuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a1-year,randomized, placebo-controlled, double-blind clinical trial. Clin. Ther.,2005,27:1164–1180.
[172] Aiello LP, Clermont A, Arora V, et al.: Inhibition of PKC β by Oral Administration ofRuboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal HemodynamicAbnormalities in Patients. Invest. Ophthalmol. Visual Sci.,2006,47:86–92.
[173] Faul MM, Gillig JR, Jirousek MR, et al.: Acyclic N-(azacycloalkyl)bisindolylmaleimides:Isozyme Selective Inhibitors of PKC. Bioorganic&Medicinal Chemistry Letters,2003,13:1857–1859.
[174] Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain ofc-Abl in complex with the small molecule inhibitors PD173955and imatinib (STI-571).Cancer Res.2002,62:4236–4243.
[175] Hancock, C.N. et al. Identification of novel extracellular signal-regulated kinase dockingdomain inhibitors. J. Med. Chem.2005,48:4586–4595.
[176] Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design:a molecular modeling perspective. Med Res Rev.,1996,16:3–50.
[177] Hann MM, Oprea TI. Pursuing the leadlikeness concept in pharma-ceutical research. CurrOpin Chem Biol.2004,8:255–263.
[178] Fink T, Bruggesser H, Reymond JL. Virtual exploration of the small-molecule chemicaluniverse below160daltons. Angew Chem Int Ed Engl.2005,44:1504–1508.
[179] Kolb HC, Sharpless KB. The growing impact of click chemistry on drug discovery. DrugDiscovery Today,2003,8,1128–1137.
[180] Whiting M, Tripp JC, Lin YC, et al.: Rapid Discovery and Structure Activity Profiling ofNovel Inhibitors of Human Immunodeficiency Virus Type1Protease Enabled by theCopper(I)-Catalyzed Synthesis of1,2,3-Triazoles and their further functionalization. J.Med.Chem.,2006,49,7697–7710.
[1] Relles. Organic chemistry in thionyl chloride. I. Dichloromaleimide chemistry. II. Thionylchloride-pyridine method for the conversion of maleimides to dichloromaleimides. HowardM. J. Org. Chem.1972,37:3630-3637.
[2] Margaret M. Faul, Kevin A. Sullivan, Leonard L. Winneroski, A geneal approach to thesynthesis of Bisindolymaleimides: Synthesis of Staurosporine Aglycone. Synthesis,1995,12:1511-1516.
[3] J. Bain, H. McLauchlan, M. Elliott and P. Cohen, Biochem. J.,2003,371:199-204.
[4] R. Li and J. A. Staford, Kinase inhibitor drugs, Wiley, Hoboken, NJ,2009.
[5] Noble ME, Endicott JA, Johnson LN. Protein Kinase Inhibitors: Insights into Drug Designfrom Structure. Science,2004,303,1800.
[1] Min Wang, Mingzhang Gao, Kathy DM, et al.: The first syntheseis of [11C]SB-216763, anew potential PET agent for imaging of glycogen synthase kinase-3(GSK-3). Bioorganic&Medicinal Chemistry Letters.2011,21,245-249.
[2] Terry VH and Michael PC. Total synthesis of Didemnimide A and B. Tetrahedron Letters.1998,39,9629-9630.
[3] Trost BM, Xie Jia, Sieber JD. The palladium catalyzed asymmetric addition of oxindoles andallenes: An atom-economical versatile method for the construction of chiral indole alkaloids.Journal of American Chemical Society,2011,133,20611-20622.
[1] Gill M, Steglich W, in Progress in the Chemistry of Organic Natural Products, ed. W. Herz, H.Grisebach, G. W. Kirby and C. Tamm, Springer-Verlag, New York,1987, vol.51, pp.1–317.
[2] W. Steglich, Pure Appl. Chem.,1989,61,281–288.
[3] Bergman J, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman, Elsevier,Amsterdam,1988, vol.1(Stereoselective synthesis, Part A), pp.3–30.
[4] Bergman J., Janosik T. and N.Wahlstrom, in Advances in Heterocyclic Chemistry, ed. A.Katritzky, Academic Press, New York,2001, vol.80, pp.1–71.
[5] Gribble GW, Berthel SJ, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman,Elsevier, Amsterdam,1993, vol.12(Stereoselective synthesis, Part H), pp.365–409.
[6] M. Prudhomme, Curr. Pharm. Des.,1997,3,265–290.
[7] M. Prudhomme, Curr. Med. Chem.,2000,7,1189–1212.
[8] M. Prudhomme, Eur. J. Med. Chem.,2003,38,123–140.
[9] Pindur U, Kim YS, Mehrabani F, Curr. Med. Chem.,1999,6,29–69.
[10] Knolker HJ, Reddy KR, Chem. Rev.,2002,102,4303–4427.
[11] Long BH, Rose WC, Vyas DM, et al.: Curr. Med. Chem.: Anti-Cancer Agents,2002,2,255–266.
[12] Kawasaki T, Higuchi K, Nat. Prod. Rep.,2005,22,761–793.
[13] anchez CS′, endez CM′, Salas JA, J. Ind. Microbiol. Biotechnol.,2006,33,560–568.
[14] Omura S, Iwai Y, Hirano A,et al.:, J. Antibiot.,1977,30,275–282.
[15] Funato N, Takayanagi H, Konda Y, et al.: Tetrahedron Lett.,1994,35,1251–1254.
[16] Link JT, Raghavan S, Gallant M, et al.: J. Am. Chem. Soc.,1996,118,2825–2842.
[17] Butler MS, Nat. Prod. Rep.,2005,22,162.
[18] Meksuriyen D, Cordell GA, J. Nat. Prod.,1988,51,893–899.
[19] Yang SW, Cordell GA, J. Nat. Prod.,1996,59,828–833.
[20] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,788–790.
[21] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,236–241.
[22] Yang SW, Lin LJ, Cordell GA, et al. J. Nat. Prod.,1999,62,1551–1553.
[24] Pearce CJ, Doyle TW, Forenza S, et al. J. Nat. Prod.,1988,51,937–940.
[23] Onaka H, Taniguchi S, Igarashi Y, et al. J. Antibiot.,2002,55,1063–1071.
[24] Anchez CS, Zhu L, Bra na AF, et al. Proc. Natl. Acad. Sci. U. S. A.,2005,102,461–466.
[25] Salas AP, Zhu L, Sáanchez C, et al. Mol. Microbiol.,2005,58,17–27.
[26](a) Liu J and Gin DY, J. Am. Chem. Soc.,2002,124,9789;(b) Honda E and Gin DY, J. Am.Chem. Soc.,2002,124,7343;(c) Tiwari P and Misra AK, J. Org. Chem.,2006,71,2911.
[27](a) Jayakanthan K and Vankar YD, Org. Lett.,2005,7,5441;(b) Saeeng R and Isobe M,Org. Lett.,2005,7,1585;(c) Lehmann U, Awasthi S and Minehan T, Org. Lett.,2003,5,2405;(d) V. Di Bussolo, M. Caselli, M. Pineschi, et al. Org. Lett.,2003,5,2173.
[28](a) Yin J, Spindler J andLinker T, Chem. Commun.,2007,2712;(b) Larrosa I, Romea P, UrpF, et al. Org. Lett.,2002,4,4651;(c) Parrish JD andLittle RD, Org. Lett.,2002,4,1439;(d)Rainier JD andCox JM, Org. Lett.,2000,2,2707;(e) Thorn SN and Gallagher T, Synlett,1996,856.
[29](a) Boulineau FP andWei A, Org. Lett.,2004,6,119;(b) Seeberger PH, Eckhardt M,Gutteridge CE, et al, J. Am. Chem. Soc.,1997,119,10064.
[30](a) Dahl RS and Finney NS, J. Am. Chem. Soc.,2004,126,8356;(b). Colinas PA and BravoRD, Org. Lett.,2003,5,4509;(c) Li BQ, Franck RW, Capozzi G, et al. Org. Lett.,1999,1,111.
[31](a) Cousins GS and Hoberg JO, Chem. Soc. Rev.,2000,29,165;(b) Haveli SD, Sridhar PR,Suguna P, et al. Org. Lett.,2007,9,1331.
[32](a) DiBussolo V, Romano MR, Pineschi M, et al. Org. Lett.,2005,7,1299;(b) Kim JY,Bussolo VD, Gin DY. Org. Lett.,2001,3,303.
[33](a) Roush WR andBennett CE, J. Am. Chem. Soc.,1999,121,3541;(b) DiBussolo V, KimY J, Gin DY, J. Am. Chem. Soc.,1998,120,13515.
[34] Lemieux RU and Ratcliffe RM, Can. J. Chem.,1979,57,1244.
[35] Roth W, Pigman W. Methods Carbohydr. Chem.1963,2,405–408.
[36] Eitelman SJ. Jordaan A. J. Chem. Soc., Chem. Commun.1977,552–553.
[37] Ireland RE, Wilcox CS, Thaisrivongs S. J. Org. Chem.1978,43,786–787.
[38] Spencer RP, Cavallaro CL, Schwartz J. J. Org. Chem.1999,64,3987–3995.
[39]Cavallaro CL, Schwart J. J. Org. Chem.1995,60,7055–7057.
[40] Hansen T, Daasbjerg K, Skrydstrup T. Tetrahedron Lett.2000,41,8645–8649.
[41] Kovács G, Micskei K, Somsák L. Carbohydr. Res.2001,336,225–228.
[42] Pollon, J. H. P.; Llewellyn, G.; Williams, J. M. Synthesis1989,758–759.
[43] Fürstner, A.; Weidmann, H. J. Carbohydr. Chem.1988,7,773–783.
[44] Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth. Commun.1992,22,2459–2477.
[45] Forbes, C. L.; Franck, R. W. J. Org. Chem.1999,64,1424–1425.
[46] Boutureira, O.; Rodríguez, M. A.; Matheu, M. I.; Díaz, Y.; Castillón, S. Org. Lett.2006,8,673–675.
[47] Micskei, K.; Juhász, Z.; Ratkovic, Z. R.; Somsák, L. Tetrahedron Lett.2006,47,6117–6120.
[48] Gómez, A. M.; Casillas, M.; Barrio, A.; Gawel, A.; López, J. C. Eur. J. Org. Chem.2008,3933–3942.
[49] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Green Chem.,2009,11,1124–1127.
[50] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Carbohydrate Research.2010,345,168–171.
[51] Subramaniam Sabesan and Susana Neira J. Org. Chem.,1991,56(18),5468-5472.
[52] Guisheng Zhang, Jie Shen, Hao Cheng, Lizhi Zhu, Lanyan Fang, Sanzhong Luo, Mark T.Muller, Gun Eui Lee, Lijun Wei, Yuguo Du, Duxin Sun, and Peng George Wang. J. Med.Chem.2005,48,2600-2611.
[53] César Sánchez, Aaroa P. Salas, Alfredo F. Bra a, et al. Chem. Commun.,2009,4118-4120.
[54] Yang M, Zhou J, Schneller SW. Tetrahedron2006,62,1295.
[55] Michel BY, Strazewski P. Tetrahedron2007,63,9836.
[56] Kumara Swamy KC, Bhuvan Kumar NN, Balaraman E, et al. Chem. Rev.2009,109,2551–2651.
[1] Wang M, Xu L, Gao MZ, et al.: Enzastaruin, the first design and radiosynthesis of a newpotential PET agent for imaging of protein kinase C. Bioorganic&Medicinal Chemistry letters.2011,21:1649-1653.
[2] Bradford VW, Radhakrishnan U, Joshua C, et al. WO2006020879.
[1] Nishzuka Y: Intracellular signaling by hydrolysis of phospholipid and activation of proteinkinase C. Science1992,258:607–614.
[2] Edelman A, Blumenthal D, Krebs E: Protein serine/threonine kinases. Annu Rev Biochem1987,56:567–613.
[3] Fantl W, Johnson, D, Williams LT: Signaling by receptor tyrosine kinases. Annu RevBiochem1993,62:453–481.
[4] Yarden Y, Ulrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem1988,57:443–478.
[5] Manning G, Whyte DB, Martinez R, et al.: The protein kinase complement of the humangenome. Science,2002,298:1912–1234.
[6] Cohen P: The role of protein phosphorylation in human health and disease. Eur J Biochem2001,268:5001–5010.
[7] G. Burnett, and E. P. Kennedy, The enzymatic phosphorylation of proteins. J Biol Chem1954,211:969–980.
[8] Uckun F, Mao C: Tyrosine kinases as new molecular targets in treatment of inflammatorydisorders and leukemia. Curr Pharm Des,2004,10:1083–1091.
[9] Knuutila S, Bjorkqvist AM, Autio K, Tarkkaqnen M, Wolf M, Monni O, et al.: DNA copynumber amplifications in human neoplasms: review of comparative genomic hybridizationstudies. Am J Pathol,1998,152:1107–1123.
[10] Noble M, Endicott J, Johnson L: Protein kinase inhibitors: insights into drug design fromstructure. Science,2004,303:1800–1805.
[11] Dancy J, Sausville EA: Issues and progress with protein kinase inhibitors for cancertreatment. Nat Rev Drug Discov,2003,2:296–313.
[12] DiGiovanna MP, Stern DF, Edgerton SM, et al.: Relationship of epidermal growth factorreceptor expression to ErbB-2signaling activity and prognosis in breast cancer patients. J ClinOncol,2005,23:1152–1160.
[13] Piccart-Gebhart M, Procter M, Leyland-Jones B, et al.: Herceptin Adjuvant (HERA) TrialStudy Team. N Engl J Med,2005,353:1659-1672.
[14] Druker B, Tamura S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosinekinase on the growth of Bcr-Abl positive cells. Nat Med,1996,2:561–566.
[15] Druker B, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of theBCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med,2001,344:1031–1037.
[16] Barker AJ, Gibson KH, Grundy W, et al.: Studies leading to the identification of ZD1839(IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitortargeted to the treatment of cancer. Bioorg Med Chem Lett,2001,11:1911–1914.
[17] Karaman M, Herrgard S, Treiber D, et al.: A quantitative analysis of kinase inhibitorselectivity. Nat Biotechnol,2008,26:127–132.
[18] Druker BJ: STI571(Gleevec) as a paradigm for cancer therapy. Trends Mol Med,2002,8(Suppl): S14–S18.
[19] Sawyer T: Novel oncogenic protein kinase inhibitors for cancer therapy. Curr Med ChemAnti-Cancer Agents,2004,4:449–455.
[20] E Ter Haar, WP Walters, S Pazhanisamy, P Taslimi, AC Pierce, GW Bemis, et al.: Kinasechemogenomics: targeting the human kinome for target validation and drug discovery. Mini RevMed Chem,2004,4:235–253.
[21] Nagar B, Bornmann WG, Pellicena P, et al.: Crystal structures of the kinase domain of c-Ablin complex with the small molecule inhibitors PD173955and imatinib (STI-571). Cancer Res,2002,62:4236–4243.
[22] Corbin A, La Rosee P, Stoffregen E, et al.: Several Bcr-Abl kinase domain mutantsassociated with imatinib mesylate resistance remain sensitive to imatinib. Blood,2003,10:4611–4614.
[23] Gorre M, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571cancer therapycaused by BCR-ABL gene mutation or amplification. Science,2001,293:876–880.
[24] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651–661.
[25] Walker E, Pacold M, Perisic O, et al.: Structural determinants of phosphoinositide3-kinaseinhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell,2000,6:909–919.
[26] Tong L, Pav S, White D, Rogers S, et al.: A highly specific inhibitor of human p38MAPkinase binds in the ATP pocket. Nat Struct Biol,1997,4:311–316.
[27] Fitzgerald C, Patel S, Becker J, et al.: Structural basis for p38alpha MAP kinasequinazolinone and pyridol-pyrimi-dine inhibitor specificity. Nat Struct Biol,2003,10:764–769.
[28] Shen G: Selective protein kinase C inhibitors and their applications. Curr Drug TargetsCardiovasc Haematol Disord,2003,3:301–307.
[29] Kim C, Xuong NH, Taylor SS: Crystal structure of a complex between the catalytic andregulatory (RIalpha) subunits of PKA. Science,2005,307:690–696.
[30] Karin M, Yamamoto Y, Wang Q: The IKK NF-kappa B system: a treasure trove for drugdevelopment. Nat Rev Drug Discov,2004,3:17–26.
[31] May M, Ghosh S: IκB kinases: kinsmen with different crafts. Science,1999,284:271-273.
[32] Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronicinflammatory diseases. N Engl J Med,1997,336:1066–1071.
[33] Haefner B: NF-kappa B: arresting a major culprit in cancer. Drug Discov Today,2002,7:653–663.
[34] Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol,2002,3:221–227.
[35] May M, D’Acquisto F, Madge L, et al.: Selective inhibition of NFkB activation by a peptidethat blocks the interaction of NEMO with the IkB kinase complex. Science,2000,289:1550–1554.
[36] Pallàs M, Verdaguer E, Jordà EG, et al.: Flavopiridol: an antitumor drug with potentialapplication in the treatment of neurodegenerative diseases. Med Hypoth,2005,64:120–123.
[37] Knockaert M, Greengard P, Meijer L: Pharmacological inhibitors of cyclin-dependentkinases. Trends Pharmacol Sci,2002,23:417–425.
[38] Pavletich NP: Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, theircyclin activators, and Cip and INK4inhibitors. J Mol Biol,1999,287:821–828.
[39] Stevenson LM, Deal MS, Hagopian JC, et al.: Activation mechanism of CDK2: role ofcyclin binding versus phosphorylation. Biochemistry,2002,41:8528-8534.
[40] Hirai H, Kawanishi N, Iwasawa Y: Recent advances in the development of selective smallmolecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem,2005,5:167–179.
[41] Jeffrey P, Tong L, Pavletich N: Structural basis of inhibition of CDK-cyclin complexes byINK4inhibitors. Genes Dev,2000,14:3115–3125.
[42] Roy KK, Sausville E: Early development of cyclin dependent kinase modulators. CurrPharm Des,2001,7:1669–1687.
[43] Parry D, Bates S, Mann DJ, et al.: Lack of cyclin D-Cdk complexes in Rb-negative cellscorrelates with high levels of p16INK4/MTS1tumour suppressor gene product. EMBO J,1995,14:503–511.
[44] Hall M, Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdkinhibitors in human cancer. Adv Cancer Res,1996,68:67–108.
[45] Zuo L, Weger J, Yang Q, et al.: Germline mutations in the p16INK4a binding domain ofCDK4in familial melanoma. Nat Genet,1996,12:97–99.
[46] Ghosh S, Liu X, Zheng Y, et al.: Rational design of potent and selective EGFR tyrosinekinase inhibitors as anticancer agents. Curr Cancer Drug Targets,2001,1:129–140.
[47] Wehrman TS, Raab WJ, Casipit CL, et al.: A system for quantifying dynamic proteininteractions defines a role for Herceptin in modulating ErbB2interactions. Proc Natl Acad SciUS,2006,103:19063–19068.
[48] Schlessinger J, Ullrich A: Growth factor signaling by receptor tyrosine kinases. Neuron1992,9:383–391.
[49] Zhu H, Iaria J, Orchard S, et al.: Epidermal growth factor receptor: association ofextracellular domain negatively regulates intracellular kinase activation in the absence of ligand.Growth Factors,2003,21:15–30.
[50] Boldt S, Kolch W: Targeting MAPK signalling: Prometheus’ fire or Pandora’s box? CurrPharm Des,2004,10:1885–1905.
[51] Kumar S, Boehm J, Lee J: p38MAP kinases: key signalling molecules as therapeutic targetsfor inflammatory diseases. Nat Rev Drug Discov,2003,2:717–726.
[52] Sebolt-Leopold J, Herrera R: Targeting the mitogen-activated protein kinase cascade to treatcancer. Nat Rev Cancer,2004,4:937–947.
[53] Pearson G, Robinson F, Beers Gibson T, et al.: Mitogen-activated protein (MAP) kinasepathways: regulation and physiological functions. Endocr Rev,2001,22:153–183.
[54] Marshall C: How do small GTPase signal transduction pathways regulate cell cycle entry?Curr Opin Cell Biol,1999,11:732–736.
[55] McMahon M, Woods D: Regulation of the p53pathway by Ras, the plot thickens. BiochimBiophys Acta,2001,1471: M63–M71.
[56] Gupta S, Barrett T, Whitmarsh AJ, et al.: Selective interaction of JNK protein kinaseisoforms with transcription factors. EMBO J,1996,15:2760–2770.
[57] Manning A, Davis R: Targeting JNK for therapeutic benefit: from junk to gold? Nat DrugDiscov,2003,2:554–565.
[58] Manning AM, Mercurio F: Transcription inhibitors in inflammation. Expert Opin InvestigDrugs,1997,6:555–567.
[59] Bennett BL, Sasaki DT, Murray BW, et al.: SP600125, an anthrapyrazolone inhibitor of JunN-terminal kinase. Proc Natl Acad Sci USA,2001,98:13681–13686.
[60] Han Z, Boyle DL, Chang L, et al.: c-Jun N-terminal kinase is required for metalloproteinaseexpression and joint destruction in inflammatory arthritis. J Clin Invest,2001,108:73–81.
[61] Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulinresistance. Nature,2002,420:333–336.
[62] Adams JL, Badger AM, Kumar S, et al: p38MAP kinase: molecular target for the inhibitionof pro-inflammatory cytokines. Prog Med Chem,2001,38:1–60.
[63] Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov2003,2:473–488.
[64] Badger AM, Bradbeer J, Votta B, et al: Pharmacological profile of SB203580, a selectiveinhibitor of cytokine suppressive binding protein/p38kinase, in animal models of arthritis, boneresorption, endotoxin shock and immune function. J Pharmacol Exp Ther,1996,279:1453–1461.
[65] Regan J, Breitfelder S, Cirillo P, et al.: Pyrazole urea-based inhibitors of p38MAP kinase:from lead compound to clinical candidate. J Med Chem,2002,45:2994–3008.
[66] Badger AM, Griswold DE, Kapadia R, et al.: Disease-modifying activity of SB242235, aselective inhibitor of p38mitogen-activated protein kinase, in rat adjuvant-induced arthritis.Arthritis Rheum,2000,43:175–183.
[67] Mclay LM, Halley F, Souness JE, et al.: The discovery of RPR200765A, a p38MAP kinaseinhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem,2001,9:537–554.
[68] Ma XL, Kumar S, Gao F, et al.: Inhibition of p38mitogen-activated protein kinase decreasescardiomyocyte apoptosis and improves cardiac function after myocardial ischemia andreperfusion. Circulation,1999,99:1685–1691.
[69] Gutkind JS: The pathways connecting G protein coupled receptors to the nucleus throughdivergent MAPK’s. J Biol Chem,1998,273:1839–1842.
[70] Wen D, Nong Y, Morgan JG, et al.: A selective small molecule IkappaB Kinase betainhibitor blocks nuclear factor kappaB-mediated inflammatory responses in humanfibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther,2006,317:989–1001.
[71] Palanki MS, Gayo-Fun L, Shevlin G, et al.: Structure-activity relationship studies of ethyl2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: aninhibitor of AP-1and NF-kappaB mediated gene expression. Bioorg Med Chem Lett,2002,12:2573–2577.
[72] Castro AC, Dang L, Soucy F, et al.: Novel IKK inhibitors: beta-carbolines. Bioorg MedChem Lett,2003,13:2419–2422.
[73] Burke JR, Pattoli MA, Gregor KR, al.: BMS-345541is a highly selective inhibitor of Ikappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependenttranscription in mice. J Biol Chem,2003,278:1450–1456.
[74] Bhat R, Budd S, Haeberlein L, et al: Glycogen synthase kinase3: a drug target for CNStherapies. J Neurochem,2004,89:1313–1317.
[75] Murphy E: Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest,2004,113:1526–1528.
[76] Coghlan MP, Culbert AA, Cross DA, et al.: Selective small molecule inhibitors of glycogensynthase kinase-3modulate glycogen metabolism and gene transcription. Chem Biol,2000,7:793–803.
[77] Mussmann R, Geese M, Harder F, et al.: Inhibition of GSK3promotes replication andsurvival of pancreatic beta cells. J Biol Chem,2007,282:12030-12037.
[78] Lucas J, Hernandez F, Gomez-Ramos P, et al.: Decreased nuclear beta-catenin, tauhyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBOJ,2001,20:27-39.
[79] Rondinone CM: Diabetes: the latest developments in inhibitors, insulin sensitisers, new drugtargets and novel approaches. October18-19,2004, The Hatton, London, UK. Expert Opin TherTargets,2005,9,415-418.
[80] Leal EC, Santiago AR, Ambrósio AF: Old and new drug targets in diabetic retinopathy:from biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNSNeurol Disord,2005,4:421–434.
[81] Beckman JA, Goldfine AB, Gordon MB, et al.: Inhibition of protein kinase Cbeta preventsimpaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res,2002,90:107–111.
[82] Meier M, King GL: Protein kinase C activation and its pharmacological inhibition invascular disease. Vasc Med,2000,5:173–185.
[83] Frank RN: Potential new medical therapies for diabetic retinopathy: protein kinase Cinhibitors. Am J Ophthalmol,2002,133:693–698.
[84] Kunkel MW, Hook KE, Howard CT, et al.: Inhibition of the epidermal growth factorreceptor tyrosine kinase by PD153035in human A431tumors in athymic nude mice. Invest NewDrug,1996,13:295-302.
[85] Woodburn JR, Barker AJ, Gibson KH, et al.: ZD1839, an epidermal growth factor tyrosinekinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res,1997,38:633-634.
[86] Zimmermann J, Buchdunger E, Mett H, et al.: Potent and selective inhibitors of the Ablkinase-phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett,1997,7:187-192.
[87] Zimmermann J, Buchdunger E, Mett H, et al.: Phenylamino-pyrimidine (PAP)-derivatives: anew class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. BioorgMed Chem Lett,1996,6:1221-1226.
[88] Zimmermann J, Caravatti G, Mett H, et al.: a new class of potent and selective inhibitors ofprotein kinase C. Arch Pharm Weinheim,1996,329:371-376.
[89] Thomas AP, inventor. Zeneca WO-09515952;1995.
[90] Davis PD, Moffat DFC, Davis JM, et al. Celltech Therapeutics WO-09719065;1997.
[91] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519774;1995.
[92] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519970;1995.
[93] Thompson AM, Bridges AJ, Fry DW, et al.: Tyrosine kinase inhibitors.7.7-amino-4-(phenylamino)-and7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines: anew class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. JMed Chem,1995,38:3780-3788.
[94] Rewcastle GF, Palmer BD, Thompson AM, et al.: Tyrosine kinase inhibitors.10. Isomeric4-[(3-bromophenyl)amino]pyrido[d]pyrimidines are potent ATP binding site inhibitors of thetyrosine kinase function of the epidermal growth factor receptor. J Med Chem,1996,39:1823-1835.
[95] Rewcastle GW, Murray DK, Elliott WL, et al.: Tyrosine kinase inhibitors.14.Structure-activity relationships for methyl-amino-substituted derivatives of4-[(3-bromophenyl)amino]-6(methylamino)-pyrido[3,4-d]pyr-imidine (PD158780), a potent andspeci c inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factor.J Med Chem,1998,41:742-751.
[96] Thompson AM, Murray DK, Elliott WL, et al.: J Med Chem,1997,40:3915-3925.
[97] Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA. J MedChem1997;40:1519.
[98] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802438;1998.
[99] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802437;1998.
[100] Cockerill GS, Guntrip SB, McKeown SK, et al., inventors. Glaxo Group WO-09713771;1997.
[101] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-19629652-A1;1998.
[102] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-1960831-A1;1997.
[103] Blankley CJ, Boschelli DH, Doherty AM, et al. Warner Lambert WO-09634867;1996.
[104] Connolly CJC, Hamby JM, Schroeder MC, et al.: Discovery and structure-activity studiesof a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. Bioorg Med Chem Lett,1997,7:2415-2418.
[105] Hamby JM, Connolly CJ, Schroeder MC, et al.: Structure-activity relationships for a novelseries of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem,1997,40:2296-2303.
[106] Mohammadi M, Froum S, Hamby JM, et al.: Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain. EMBO J,1998,17:5896-5904.
[107] Panek RL, Lu GH, Klutchko SR, et al.: a new nanomolar potent and broadly active proteinkinase inhibitor. J Pharmacol Exp Ther,1997,283:1433-1444.
[108] Boschelli DH, Wu Z, Klutchko SR, et al.: synthesis and tyrosine kinase inhibitory activityof a series of2-amino-8H-pyrido[2,3-d]pyrimidines: identigication of potent, selectiveplatelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem,1998,41:4365-4377.
[109] Rewcastle GF, Bridges AJ, Fry DW, et al.: Tyrosine Kinase Inhibitors.12. Synthesis andStructure-Activity Relationships for6-Substituted4-(Phenylamino) pyrimido[5,4-d] pyrimidinesDesigned as Inhibitors of the Epidermal Growth Factor Receptor. J Med Chem,1997,40:1820-1826.
[110] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae WO-09732880;1997.
[111] Himmelsbach F, Dahmann G, von Ruden T, et al. WO-09732882;1997.
[112] Traxler P, Bold G, Buchdunger E, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[113] Missbach M, Jeschke M, Field JB, et al.: A novel inhibitor of the tyrosine kinase Srcsuppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitroand in rodent models in vivo. Bone,1999,24:437-449.
[114] Missbach M, Green J, Susa M, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[115] Altmann E, inventor. Novartis AG WO-09734895;1997.
[116] Altmann E, Missbach M, Widler L. Novartis AG WO-09732879;1997.
[117] Altmann E, Missbach M, Widler L, et al. Novartis AG WO-09749706;1997.
[118] Altmann E, Widler L, Missbach M. Novartis AG WO-09728161;1997.
[119] Missbach M. Ciba–Geigy WO-09610028;1996.
[120] Henry JR, Rupert KC, Dodd JH, et al.:6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (RWJ68354): A Potent and Selective p38KinaseInhibitor J Med Chem,1998,41:4196-4198.
[121] Hanke JH, Gardner JP, Dow RL, et al.: Discovery of a novel, potent, and Srcfamily-selective tyrosine kinase Inhibitor: study of Lck-and FynT-dependent T cell activation. JBiol Chem,1996,271:695-701.
[122] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651-661.
[123] Bishop AC, Kung CY, Shah K, et al.: Generation of monospecific nanomolar tyrosinekinase inhibitors via a chemical genetic approach. J Am Chem Soc,1999,121:627-631.
[124] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814451;1998.
[125] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814449;1998.
[126] Tang PC, Sun L, McMahon G, et al. Sugen WO-09850356;1998.
[127] Tang C, Sun L, McMahon G, et al. Sugen WO-09807695;1998.
[128] Sun L, Tran F, App H, et al.: Synthesis and biological evaluations of3-substitutedindolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity towardparticular receptor tyrosine kinases. J Med Chem,1998,41:2588-2603.
[129] Battistini C, Ermoli A, Vioglio S, et al. Pharmacia&Upjohn WO-09745409;1997.
[130] Battistini C, Vioglio S, Buzzetti F, et al. Pharmacia&Upjohn WO-09746551;1997.
[131] McNutt RW, Jung DK, Harris PA, et al., inventors. Glaxo Group WO-09910325;1999.
[132] Lackey K, Chapman D, Crosby RM, et al. Proc Am Assoc Cancer Res1999;40:124.
[133] Davis ST, Dickerson SH, Frye SV, et al. Glaxo Group WO-09915500;1999.
[134] Luzzio MJ, Bramson N, Dickerson S, et al. Proc Am Assoc Cancer Res,1999,40:622.
[135] Parker CW, Entsch B, Letham DS. Inhibitors of cytokinin metabolism I. Inhibition of twoenzymes which metabo-lize cytokinins. Phytochem,1986,25:303-310.
[136] Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol,1996,6:393-397.
[137] Vesely J, Havlicek L, Strnad M, et al. Progress in Cell Cycle Research. Eur J Biochem1994,224:771-786.
[138] MacCallum DE, Melville J, Frame S, et al.: Seliciclib (CYC202, R-Roscovitine) inducescell death in multi-ple myeloma cells by inhibition of RNA polymerase II-dependenttranscription and down-regulation of Mcl-1Cancer Research,2005,65(12):5399–5407.
[139] Noopur Raje, Shaji Kumar, Teru Hideshima, et al.: Seliciclib (CYC202or R-roscovitine), asmall-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation ofMcl-1in multiple myeloma. Blood,2005,106(3):1042–1047.
[140] Rossi AG, Sawatzky DA, Walker A, et al.: Cyclin-dependent kinase inhibitors enhance theresolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine,2006,12(9):1056–1064.
[141] Gray NS, Wodicka L, Thunnissen AMWH, et al.: Exploiting chemical libraries, structure,and genomics in the search for kinase inhibitors. Science,1998,281:533-538.
[142] Imbach P, Capraro HG, Furet P, et al.:2,6,9-trisubstituted purines: optimization towardshighly potent and selective CDK1inhibitors. Bioorg Med Chem Lett,1999,9:91-96.
[143] Adams JL, Boehm JC, Kassis S, et al.: Pyrimidinylimidazole inhibitors of CSBP/p38kinase demonstrating decreased inhibition of hepatic cytochrome P450enzymes. Bioorg MedChem Lett,1998,8:3111-3116.
[144] Jackson JR, Bolognese B, Hillegass L, et al.: Pharmacological Effects of SB220025, aSelective Inhibitor of P38Mitogen-Activated Protein Kinase, in Angiogenesis and ChronicInflammatory Disease Models. J Pharmacol Exp Ther,1998,284:687-692.
[145] Frantz B, Klatt T, Pang M, et al.: Induction of apoptosis by SB202190through inhibitionof p38β mitogen-activated protein kinase. Biochem,1998,37:13846-13853.
[146] Liverton NJ, Butcher JW, Clairbone CF, et al.: Design and Synthesis of Potent, Selective,and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38Mitogen-Activated ProteinKinase. J Med Chem,1999,42:2180-2190.
[147] Heimbrook DC, Huber HE, Stirdivant SM, et al.: Epidermal growth factor induction of thec-jun promoter by a Rac pathway. Proc Am Assoc Cancer Res,1998,39:558-559.
[148] Meyer T, Regenass U, Fabbro D, et al.: A derivative of staurosporine (CGP41251) showsselectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivoanti-tumor activity. Int J Cancer,1989,43:85-856.
[149] Mehta AB, Virchis AE, Jones DT, et al.: The formation of new blood vessels from anexisting vascular network. Blood,1997,90:3634-3641.
[150] P. A. Campochiaro and the C99-PKC412-003Study Group, Invest. Ophthalmol. VisualSci.,2004,45:922–931.
[151] Takahashi I, Kobayashi E, Asano K, et al. UCN-01, a selective inhibitor of protein kinaseC from Streptomyces. J Antibiot,1987,40:1782-1784.
[152] Akinaga S, Sugiyama K, Akiyama T. UCN-01(7-hydroxystaurosporine) and otherindolocarbazole compounds: a new generation of anti-cancer agents for the new century?.Anti-Cancer Drug Des,2000,15:43–52.
[153] K. Grosios, UCN-01Kyowa Hakko Kogyo Co. Curr. Opin. Invest. Drugs (Thomson Sci.),2001,2:287–297.
[154] Senderowicz AM. The Cell Cycle as a Target for Cancer Therapy: Basic and ClinicalFindings with the Small Molecule Inhibitors Flavopiridol and UCN-01. Oncologist,2002,7(suppl.3),12–19.
[155] Butler MS. Natural products to drugs: natural product derived compounds in clinical trials.Nat. Prod. Rep.,2005,22:162–195.
[156] ClinicalTrials.gov (a service of the US National Institutes of Health). Available athttp://clinicaltrials.gov.
[157] Fuse E, Kuwabara T, Sparreboom A, et al.: Review of UCN-01development: a lesson inthe importance of clinical pharmacology. J. Clin. Pharmacol,2005,45:394–403.
[158] Sausville EA. Indifferently Pursued or Unowned Drugs: Who Should Lead WhereCompanies Do Not Tread?. J. Clin. Oncol,2005,23:1796–1798.
[159] Camoratto AM, Jani J P, Angeles TS, et al.: CEP-751inhibits trk receptor tyrosine kinaseactivity in vitro and exhibits anti-tumor activity. Int. J. Cancer,1997,72:673–679.
[160] Ruggeri BA, Miknyoczki SJ, Singh J, et al.: Role of neurotrophin–trk interactions inoncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors inpre-clinical tumor models. Curr. Med. Chem.,1999,6:845–857.
[161] Strock CJ, Park JI, Rosen DM, et al.: Activity of irinotecan and the tyrosine kinaseinhibitor CEP-751in medullary thyroid cancer. J Clin Endocrinol Metab. J. Clin. Endocrinol.Metab.,2006,91:79–84.
[162] Strock CJ, Park JI, Rosen M, et al.: Activated RET Tyrosine Kinase Activity and BlockMedullary Thyroid Carcinoma Cell Growth. Cancer Res.,2003,63:5559–5563.
[163] Brown P, Levis M, McIntyre E, et al.: Constitutively activated FLT3phosphorylates BADpartially through pim-1. Leukemia,2006,20:1368–1376.
[164] Smith BD, Levis M, Beran M, et al.: Single Agent CEP-701, a novel FLT3inhibitor, showsbiologic response and clinical activity in patients with relapsed or refractory acute myeloidleukemia. Blood,2004,103:3669–3676.
[165] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.Invest. New Drugs,2004,22:449–458.
[166] Camoratto AM, Jani JP, Angeles T, Maroney A, et al.: CEP-751inhibits trk receptortyrosine kinase activity in vitro and exhibits anti-tumor activity. Int J Cancer,1997,72:673-679.
[167] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.Invest. New Drugs,2004,22:449–458.
[168] Gingrich DE, Reddy DR, Iqbal MA, et al.: A New Class of Potent Vascular EndothelialGrowth Factor Receptor Tyrosine Kinase Inhibitors: Structure Activity Relationships for aSeries of9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo [3,4-c]carbazole-5-onesand the Identification of CEP-5214and Its Dimethylglycine Ester Prodrug Clinical CandidateCEP-7055. J. Med. Chem.,2003,46:5375–5388.
[169] Jirousek MR, Gillig JR, Gonzalez CM, et al.:(S)-13-[(Dimethylamino)methyl]-10,11,14,15–tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues: Isozyme Selective Inhibitors ofProtein Kinase Cβ. J. Med. Chem.,1996,39:2664–2671.
[170] Tuttle KR, Bakris GL, Toto RD, et al.: The Effect of Ruboxistaurin on Nephropathy inType2Diabetes. Diabetes Care,2005,28:2686–2690.
[171] Vinik AI, Bril V, Kempler P, et al.: Treatment of symptomatic diabetic peripheralneuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a1-year,randomized, placebo-controlled, double-blind clinical trial. Clin. Ther.,2005,27:1164–1180.
[172] Aiello LP, Clermont A, Arora V, et al.: Inhibition of PKC β by Oral Administration ofRuboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal HemodynamicAbnormalities in Patients. Invest. Ophthalmol. Visual Sci.,2006,47:86–92.
[173] Faul MM, Gillig JR, Jirousek MR, et al.: Acyclic N-(azacycloalkyl)bisindolylmaleimides:Isozyme Selective Inhibitors of PKC. Bioorganic&Medicinal Chemistry Letters,2003,13:1857–1859.
[174] Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain ofc-Abl in complex with the small molecule inhibitors PD173955and imatinib (STI-571). CancerRes.2002,62:4236–4243.
[175] Hancock, C.N. et al. Identification of novel extracellular signal-regulated kinase dockingdomain inhibitors. J. Med. Chem.2005,48:4586–4595.
[176] Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design:a molecular modeling perspective. Med Res Rev.,1996,16:3–50.
[177] Hann MM, Oprea TI. Pursuing the leadlikeness concept in pharma-ceutical research. CurrOpin Chem Biol.2004,8:255–263.
[178] Fink T, Bruggesser H, Reymond JL. Virtual exploration of the small-molecule chemicaluniverse below160daltons. Angew Chem Int Ed Engl.2005,44:1504–1508.
[179] Kolb HC, Sharpless KB. The growing impact of click chemistry on drug discovery. DrugDiscovery Today,2003,8,1128–1137.
[180] Whiting M, Tripp JC, Lin YC, et al.: Rapid Discovery and Structure Activity Profiling ofNovel Inhibitors of Human Immunodeficiency Virus Type1Protease Enabled by theCopper(I)-Catalyzed Synthesis of1,2,3-Triazoles and their further functionalization. J.Med.Chem.,2006,49,7697–7710.
[181] Relles. Organic chemistry in thionyl chloride. I. Dichloromaleimide chemistry. II. Thionylchloride-pyridine method for the conversion of maleimides to dichloromaleimides. Howard M. J.Org. Chem.1972,37:3630-3637.
[182] Margaret M. Faul, Kevin A. Sullivan, Leonard L. Winneroski, A geneal approach to thesynthesis of Bisindolymaleimides: Synthesis of Staurosporine Aglycone. Synthesis,1995,12:1511-1516.
[183] J. Bain, H. McLauchlan, M. Elliott and P. Cohen, Biochem. J.,2003,371:199-204.
[184] R. Li and J. A. Staford, Kinase inhibitor drugs, Wiley, Hoboken, NJ,2009.
[185] Noble ME, Endicott JA, Johnson LN. Protein Kinase Inhibitors: Insights into Drug Designfrom Structure. Science,2004,303,1800.
[186] Gill M, Steglich W, in Progress in the Chemistry of Organic Natural Products, ed. W. Herz,H. Grisebach, G. W. Kirby and C. Tamm, Springer-Verlag, New York,1987, vol.51, pp.1–317.
[187] W. Steglich, Pure Appl. Chem.,1989,61,281–288.
[188] Bergman J, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman, Elsevier,Amsterdam,1988, vol.1(Stereoselective synthesis, Part A), pp.3–30.
[189] Bergman J., Janosik T. and N.Wahlstrom, in Advances in Heterocyclic Chemistry, ed. A.Katritzky, Academic Press, New York,2001, vol.80, pp.1–71.
[190] Gribble GW, Berthel SJ, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman,Elsevier, Amsterdam,1993, vol.12(Stereoselective synthesis, Part H), pp.365–409.
[191] M. Prudhomme, Curr. Pharm. Des.,1997,3,265–290.
[192] M. Prudhomme, Curr. Med. Chem.,2000,7,1189–1212.
[193] M. Prudhomme, Eur. J. Med. Chem.,2003,38,123–140.
[194] Pindur U, Kim YS, Mehrabani F, Curr. Med. Chem.,1999,6,29–69.
[195] Knolker HJ, Reddy KR, Chem. Rev.,2002,102,4303–4427.
[196] Long BH, Rose WC, Vyas DM, et al.: Curr. Med. Chem.: Anti-Cancer Agents,2002,2,255–266.
[197] Kawasaki T, Higuchi K, Nat. Prod. Rep.,2005,22,761–793.
[198] anchez CS′, endez CM′, Salas JA, J. Ind. Microbiol. Biotechnol.,2006,33,560–568.
[199] Omura S, Iwai Y, Hirano A,et al.:, J. Antibiot.,1977,30,275–282.
[200] Funato N, Takayanagi H, Konda Y, et al.: Tetrahedron Lett.,1994,35,1251–1254.
[201] Link JT, Raghavan S, Gallant M, et al.: J. Am. Chem. Soc.,1996,118,2825–2842.
[202] Butler MS, Nat. Prod. Rep.,2005,22,162.
[203] Meksuriyen D, Cordell GA, J. Nat. Prod.,1988,51,893–899.
[204] Yang SW, Cordell GA, J. Nat. Prod.,1996,59,828–833.
[205] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,788–790.
[206] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,236–241.
[207] Yang SW, Lin LJ, Cordell GA, et al. J. Nat. Prod.,1999,62,1551–1553.
[208] Pearce CJ, Doyle TW, Forenza S, et al. J. Nat. Prod.,1988,51,937–940.
[209] Onaka H, Taniguchi S, Igarashi Y, et al. J. Antibiot.,2002,55,1063–1071.
[210] Anchez CS, Zhu L, Bra na AF, et al. Proc. Natl. Acad. Sci. U. S. A.,2005,102,461–466.
[211] Salas AP, Zhu L, Sáanchez C, et al. Mol. Microbiol.,2005,58,17–27.
[212](a) Liu J and Gin DY, J. Am. Chem. Soc.,2002,124,9789;(b) Honda E and Gin DY, J.Am. Chem. Soc.,2002,124,7343;(c) Tiwari P and Misra AK, J. Org. Chem.,2006,71,2911.
[213](a) Jayakanthan K and Vankar YD, Org. Lett.,2005,7,5441;(b) Saeeng R and Isobe M,Org. Lett.,2005,7,1585;(c) Lehmann U, Awasthi S and Minehan T, Org. Lett.,2003,5,2405;(d) V. Di Bussolo, M. Caselli, M. Pineschi, et al. Org. Lett.,2003,5,2173.
[214](a) Yin J, Spindler J andLinker T, Chem. Commun.,2007,2712;(b) Larrosa I, Romea P,Urp F, et al. Org. Lett.,2002,4,4651;(c) Parrish JD andLittle RD, Org. Lett.,2002,4,1439;(d)Rainier JD andCox JM, Org. Lett.,2000,2,2707;(e) Thorn SN and Gallagher T, Synlett,1996,856.
[215](a) Boulineau FP andWei A, Org. Lett.,2004,6,119;(b) Seeberger PH, Eckhardt M,Gutteridge CE, et al, J. Am. Chem. Soc.,1997,119,10064.
[216](a) Dahl RS and Finney NS, J. Am. Chem. Soc.,2004,126,8356;(b). Colinas PA andBravo RD, Org. Lett.,2003,5,4509;(c) Li BQ, Franck RW, Capozzi G, et al. Org. Lett.,1999,1,111.
[217](a) Cousins GS and Hoberg JO, Chem. Soc. Rev.,2000,29,165;(b) Haveli SD, SridharPR, Suguna P, et al. Org. Lett.,2007,9,1331.
[218](a) DiBussolo V, Romano MR, Pineschi M, et al. Org. Lett.,2005,7,1299;(b) Kim JY,Bussolo VD, Gin DY. Org. Lett.,2001,3,303.
[219](a) Roush WR andBennett CE, J. Am. Chem. Soc.,1999,121,3541;(b) DiBussolo V, KimY J, Gin DY, J. Am. Chem. Soc.,1998,120,13515.
[220] Lemieux RU and Ratcliffe RM, Can. J. Chem.,1979,57,1244.
[221] Roth W, Pigman W. Methods Carbohydr. Chem.1963,2,405–408.
[223] Eitelman SJ. Jordaan A. J. Chem. Soc., Chem. Commun.1977,552–553.
[224] Ireland RE, Wilcox CS, Thaisrivongs S. J. Org. Chem.1978,43,786–787.
[225] Spencer RP, Cavallaro CL, Schwartz J. J. Org. Chem.1999,64,3987–3995.
[226]Cavallaro CL, Schwart J. J. Org. Chem.1995,60,7055–7057.
[227] Hansen T, Daasbjerg K, Skrydstrup T. Tetrahedron Lett.2000,41,8645–8649.
[228] Kovács G, Micskei K, Somsák L. Carbohydr. Res.2001,336,225–228.
[229] Pollon, J. H. P.; Llewellyn, G.; Williams, J. M. Synthesis1989,758–759.
[230] Fürstner, A.; Weidmann, H. J. Carbohydr. Chem.1988,7,773–783.
[231] Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth. Commun.1992,22,2459–2477.
[232] Forbes, C. L.; Franck, R. W. J. Org. Chem.1999,64,1424–1425.
[233] Boutureira, O.; Rodríguez, M. A.; Matheu, M. I.; Díaz, Y.; Castillón, S. Org. Lett.2006,8,673–675.
[234] Micskei, K.; Juhász, Z.; Ratkovic, Z. R.; Somsák, L. Tetrahedron Lett.2006,47,6117–6120.
[235] Gómez, A. M.; Casillas, M.; Barrio, A.; Gawel, A.; López, J. C. Eur. J. Org. Chem.2008,3933–3942.
[236] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Green Chem.,2009,11,1124–1127.
[237] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Carbohydrate Research.2010,345,168–171.
[238] Subramaniam Sabesan and Susana Neira J. Org. Chem.,1991,56(18),5468-5472.
[239] Guisheng Zhang, Jie Shen, Hao Cheng, Lizhi Zhu, Lanyan Fang, Sanzhong Luo, Mark T.Muller, Gun Eui Lee, Lijun Wei, Yuguo Du, Duxin Sun, and Peng George Wang. J. Med. Chem.2005,48,2600-2611.
[240] César Sánchez, Aaroa P. Salas, Alfredo F. Bra a, et al. Chem. Commun.,2009,4118-4120.
[241] Yang M, Zhou J, Schneller SW. Tetrahedron2006,62,1295.
[242] Michel BY, Strazewski P. Tetrahedron2007,63,9836.
[243] Kumara Swamy KC, Bhuvan Kumar NN, Balaraman E, et al. Chem. Rev.2009,109,2551–2651.
[244] Wang M, Xu L, Gao MZ, et al.: Enzastaruin, the first design and radiosynthesis of a newpotential PET agent for imaging of protein kinase C. Bioorganic&Medicinal Chemistry letters.2011,21:1649-1653.
[245] Bradford VW, Radhakrishnan U, Joshua C, et al. WO2006020879
[2] Edelman A, Blumenthal D, Krebs E: Protein serine/threonine kinases. Annu Rev Biochem1987,56:567–613.
[3] Fantl W, Johnson, D, Williams LT: Signaling by receptor tyrosine kinases. Annu RevBiochem1993,62:453–481.
[4] Yarden Y, Ulrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem1988,57:443–478.
[5] Manning G, Whyte DB, Martinez R, et al.: The protein kinase complement of the humangenome. Science,2002,298:1912–1234.
[6] Cohen P: The role of protein phosphorylation in human health and disease. Eur J Biochem2001,268:5001–5010.
[7] G. Burnett, and E. P. Kennedy, The enzymatic phosphorylation of proteins. J Biol Chem1954,211:969–980.
[8] Uckun F, Mao C: Tyrosine kinases as new molecular targets in treatment of inflammatorydisorders and leukemia. Curr Pharm Des,2004,10:1083–1091.
[9] Knuutila S, Bjorkqvist AM, Autio K, Tarkkaqnen M, Wolf M, Monni O, et al.: DNA copynumber amplifications in human neoplasms: review of comparative genomic hybridizationstudies. Am J Pathol,1998,152:1107–1123.
[10] Noble M, Endicott J, Johnson L: Protein kinase inhibitors: insights into drug design fromstructure. Science,2004,303:1800–1805.
[11] Dancy J, Sausville EA: Issues and progress with protein kinase inhibitors for cancertreatment. Nat Rev Drug Discov,2003,2:296–313.
[12] DiGiovanna MP, Stern DF, Edgerton SM, et al.: Relationship of epidermal growth factorreceptor expression to ErbB-2signaling activity and prognosis in breast cancer patients. JClin Oncol,2005,23:1152–1160.
[13] Piccart-Gebhart M, Procter M, Leyland-Jones B, et al.: Herceptin Adjuvant (HERA) TrialStudy Team. N Engl J Med,2005,353:1659-1672.
[14] Druker B, Tamura S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosinekinase on the growth of Bcr-Abl positive cells. Nat Med,1996,2:561–566.
[15] Druker B, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of theBCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med,2001,344:1031–1037.
[16] Barker AJ, Gibson KH, Grundy W, et al.: Studies leading to the identification of ZD1839(IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinaseinhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett,2001,11:1911–1914.
[17] Karaman M, Herrgard S, Treiber D, et al.: A quantitative analysis of kinase inhibitorselectivity. Nat Biotechnol,2008,26:127–132.
[18] Druker BJ: STI571(Gleevec) as a paradigm for cancer therapy. Trends Mol Med,2002,8(Suppl): S14–S18.
[19] Sawyer T: Novel oncogenic protein kinase inhibitors for cancer therapy. Curr Med ChemAnti-Cancer Agents,2004,4:449–455.
[20] E Ter Haar, WP Walters, S Pazhanisamy, P Taslimi, AC Pierce, GW Bemis, et al.: Kinasechemogenomics: targeting the human kinome for target validation and drug discovery. MiniRev Med Chem,2004,4:235–253.
[21] Nagar B, Bornmann WG, Pellicena P, et al.: Crystal structures of the kinase domain of c-Ablin complex with the small molecule inhibitors PD173955and imatinib (STI-571). CancerRes,2002,62:4236–4243.
[22] Corbin A, La Rosee P, Stoffregen E, et al.: Several Bcr-Abl kinase domain mutantsassociated with imatinib mesylate resistance remain sensitive to imatinib. Blood,2003,10:4611–4614.
[23] Gorre M, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571cancer therapycaused by BCR-ABL gene mutation or amplification. Science,2001,293:876–880.
[24] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651–661.
[25] Walker E, Pacold M, Perisic O, et al.: Structural determinants of phosphoinositide3-kinaseinhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell,2000,6:909–919.
[26] Tong L, Pav S, White D, Rogers S, et al.: A highly specific inhibitor of human p38MAPkinase binds in the ATP pocket. Nat Struct Biol,1997,4:311–316.
[27] Fitzgerald C, Patel S, Becker J, et al.: Structural basis for p38alpha MAP kinasequinazolinone and pyridol-pyrimi-dine inhibitor specificity. Nat Struct Biol,2003,10:764–769.
[28] Shen G: Selective protein kinase C inhibitors and their applications. Curr Drug TargetsCardiovasc Haematol Disord,2003,3:301–307.
[29] Kim C, Xuong NH, Taylor SS: Crystal structure of a complex between the catalytic andregulatory (RIalpha) subunits of PKA. Science,2005,307:690–696.
[30] Karin M, Yamamoto Y, Wang Q: The IKK NF-kappa B system: a treasure trove for drugdevelopment. Nat Rev Drug Discov,2004,3:17–26.
[31] May M, Ghosh S: IκB kinases: kinsmen with different crafts. Science,1999,284:271-273.
[32] Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronicinflammatory diseases. N Engl J Med,1997,336:1066–1071.
[33] Haefner B: NF-kappa B: arresting a major culprit in cancer. Drug Discov Today,2002,7:653–663.
[34] Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol,2002,3:221–227.
[35] May M, D’Acquisto F, Madge L, et al.: Selective inhibition of NFkB activation by a peptidethat blocks the interaction of NEMO with the IkB kinase complex. Science,2000,289:1550–1554.
[36] Pallàs M, Verdaguer E, Jordà EG, et al.: Flavopiridol: an antitumor drug with potentialapplication in the treatment of neurodegenerative diseases. Med Hypoth,2005,64:120–123.
[37] Knockaert M, Greengard P, Meijer L: Pharmacological inhibitors of cyclin-dependentkinases. Trends Pharmacol Sci,2002,23:417–425.
[38] Pavletich NP: Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, theircyclin activators, and Cip and INK4inhibitors. J Mol Biol,1999,287:821–828.
[39] Stevenson LM, Deal MS, Hagopian JC, et al.: Activation mechanism of CDK2: role ofcyclin binding versus phosphorylation. Biochemistry,2002,41:8528-8534.
[40] Hirai H, Kawanishi N, Iwasawa Y: Recent advances in the development of selective smallmolecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem,2005,5:167–179.
[41] Jeffrey P, Tong L, Pavletich N: Structural basis of inhibition of CDK-cyclin complexes byINK4inhibitors. Genes Dev,2000,14:3115–3125.
[42] Roy KK, Sausville E: Early development of cyclin dependent kinase modulators. CurrPharm Des,2001,7:1669–1687.
[43] Parry D, Bates S, Mann DJ, et al.: Lack of cyclin D-Cdk complexes in Rb-negative cellscorrelates with high levels of p16INK4/MTS1tumour suppressor gene product. EMBO J,1995,14:503–511.
[44] Hall M, Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdkinhibitors in human cancer. Adv Cancer Res,1996,68:67–108.
[45] Zuo L, Weger J, Yang Q, et al.: Germline mutations in the p16INK4a binding domain ofCDK4in familial melanoma. Nat Genet,1996,12:97–99.
[46] Ghosh S, Liu X, Zheng Y, et al.: Rational design of potent and selective EGFR tyrosinekinase inhibitors as anticancer agents. Curr Cancer Drug Targets,2001,1:129–140.
[47] Wehrman TS, Raab WJ, Casipit CL, et al.: A system for quantifying dynamic proteininteractions defines a role for Herceptin in modulating ErbB2interactions. Proc Natl AcadSci US,2006,103:19063–19068.
[48] Schlessinger J, Ullrich A: Growth factor signaling by receptor tyrosine kinases. Neuron1992,9:383–391.
[49] Zhu H, Iaria J, Orchard S, et al.: Epidermal growth factor receptor: association ofextracellular domain negatively regulates intracellular kinase activation in the absence ofligand. Growth Factors,2003,21:15–30.
[50] Boldt S, Kolch W: Targeting MAPK signalling: Prometheus’ fire or Pandora’s box? CurrPharm Des,2004,10:1885–1905.
[51] Kumar S, Boehm J, Lee J: p38MAP kinases: key signalling molecules as therapeutic targetsfor inflammatory diseases. Nat Rev Drug Discov,2003,2:717–726.
[52] Sebolt-Leopold J, Herrera R: Targeting the mitogen-activated protein kinase cascade to treatcancer. Nat Rev Cancer,2004,4:937–947.
[53] Pearson G, Robinson F, Beers Gibson T, et al.: Mitogen-activated protein (MAP) kinasepathways: regulation and physiological functions. Endocr Rev,2001,22:153–183.
[54] Marshall C: How do small GTPase signal transduction pathways regulate cell cycle entry?Curr Opin Cell Biol,1999,11:732–736.
[55] McMahon M, Woods D: Regulation of the p53pathway by Ras, the plot thickens. BiochimBiophys Acta,2001,1471: M63–M71.
[56] Gupta S, Barrett T, Whitmarsh AJ, et al.: Selective interaction of JNK protein kinaseisoforms with transcription factors. EMBO J,1996,15:2760–2770.
[57] Manning A, Davis R: Targeting JNK for therapeutic benefit: from junk to gold? Nat DrugDiscov,2003,2:554–565.
[58] Manning AM, Mercurio F: Transcription inhibitors in inflammation. Expert Opin InvestigDrugs,1997,6:555–567.
[59] Bennett BL, Sasaki DT, Murray BW, et al.: SP600125, an anthrapyrazolone inhibitor of JunN-terminal kinase. Proc Natl Acad Sci USA,2001,98:13681–13686.
[60] Han Z, Boyle DL, Chang L, et al.: c-Jun N-terminal kinase is required for metalloproteinaseexpression and joint destruction in inflammatory arthritis. J Clin Invest,2001,108:73–81.
[61] Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulinresistance. Nature,2002,420:333–336.
[62] Adams JL, Badger AM, Kumar S, et al: p38MAP kinase: molecular target for the inhibitionof pro-inflammatory cytokines. Prog Med Chem,2001,38:1–60.
[63] Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov2003,2:473–488.
[64] Badger AM, Bradbeer J, Votta B, et al: Pharmacological profile of SB203580, a selectiveinhibitor of cytokine suppressive binding protein/p38kinase, in animal models of arthritis,bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther,1996,279:1453–1461.
[65] Regan J, Breitfelder S, Cirillo P, et al.: Pyrazole urea-based inhibitors of p38MAP kinase:from lead compound to clinical candidate. J Med Chem,2002,45:2994–3008.
[66] Badger AM, Griswold DE, Kapadia R, et al.: Disease-modifying activity of SB242235, aselective inhibitor of p38mitogen-activated protein kinase, in rat adjuvant-induced arthritis.Arthritis Rheum,2000,43:175–183.
[67] Mclay LM, Halley F, Souness JE, et al.: The discovery of RPR200765A, a p38MAP kinaseinhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem,2001,9:537–554.
[68] Ma XL, Kumar S, Gao F, et al.: Inhibition of p38mitogen-activated protein kinase decreasescardiomyocyte apoptosis and improves cardiac function after myocardial ischemia andreperfusion. Circulation,1999,99:1685–1691.
[69] Gutkind JS: The pathways connecting G protein coupled receptors to the nucleus throughdivergent MAPK’s. J Biol Chem,1998,273:1839–1842.
[70] Wen D, Nong Y, Morgan JG, et al.: A selective small molecule IkappaB Kinase betainhibitor blocks nuclear factor kappaB-mediated inflammatory responses in humanfibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther,2006,317:989–1001.
[71] Palanki MS, Gayo-Fun L, Shevlin G, et al.: Structure-activity relationship studies of ethyl2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate:an inhibitor of AP-1and NF-kappaB mediated gene expression. Bioorg Med Chem Lett,2002,12:2573–2577.
[72] Castro AC, Dang L, Soucy F, et al.: Novel IKK inhibitors: beta-carbolines. Bioorg MedChem Lett,2003,13:2419–2422.
[73] Burke JR, Pattoli MA, Gregor KR, al.: BMS-345541is a highly selective inhibitor of Ikappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappaB-dependent transcription in mice. J Biol Chem,2003,278:1450–1456.
[74] Bhat R, Budd S, Haeberlein L, et al: Glycogen synthase kinase3: a drug target for CNStherapies. J Neurochem,2004,89:1313–1317.
[75] Murphy E: Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest,2004,113:1526–1528.
[76] Coghlan MP, Culbert AA, Cross DA, et al.: Selective small molecule inhibitors of glycogensynthase kinase-3modulate glycogen metabolism and gene transcription. Chem Biol,2000,7:793–803.
[77] Mussmann R, Geese M, Harder F, et al.: Inhibition of GSK3promotes replication andsurvival of pancreatic beta cells. J Biol Chem,2007,282:12030-12037.
[78] Lucas J, Hernandez F, Gomez-Ramos P, et al.: Decreased nuclear beta-catenin, tauhyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.EMBO J,2001,20:27-39.
[79] Rondinone CM: Diabetes: the latest developments in inhibitors, insulin sensitisers, new drugtargets and novel approaches. October18-19,2004, The Hatton, London, UK. Expert OpinTher Targets,2005,9,415-418.
[80] Leal EC, Santiago AR, Ambrósio AF: Old and new drug targets in diabetic retinopathy:from biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNSNeurol Disord,2005,4:421–434.
[81] Beckman JA, Goldfine AB, Gordon MB, et al.: Inhibition of protein kinase Cbeta preventsimpaired endothelium-dependent vasodilation caused by hyperglycemia in humans. CircRes,2002,90:107–111.
[82] Meier M, King GL: Protein kinase C activation and its pharmacological inhibition invascular disease. Vasc Med,2000,5:173–185.
[83] Frank RN: Potential new medical therapies for diabetic retinopathy: protein kinase Cinhibitors. Am J Ophthalmol,2002,133:693–698.
[84] Kunkel MW, Hook KE, Howard CT, et al.: Inhibition of the epidermal growth factorreceptor tyrosine kinase by PD153035in human A431tumors in athymic nude mice. InvestNew Drug,1996,13:295-302.
[85] Woodburn JR, Barker AJ, Gibson KH, et al.: ZD1839, an epidermal growth factor tyrosinekinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res,1997,38:633-634.
[86] Zimmermann J, Buchdunger E, Mett H, et al.: Potent and selective inhibitors of the Ablkinase-phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett,1997,7:187-192.
[87] Zimmermann J, Buchdunger E, Mett H, et al.: Phenylamino-pyrimidine (PAP)-derivatives: anew class of potent and highly selective PDGF-receptor autophosphorylation inhibitors.Bioorg Med Chem Lett,1996,6:1221-1226.
[88] Zimmermann J, Caravatti G, Mett H, et al.: a new class of potent and selective inhibitors ofprotein kinase C. Arch Pharm Weinheim,1996,329:371-376.
[89] Thomas AP, inventor. Zeneca WO-09515952;1995.
[90] Davis PD, Moffat DFC, Davis JM, et al. Celltech Therapeutics WO-09719065;1997.
[91] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519774;1995.
[92] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519970;1995.
[93] Thompson AM, Bridges AJ, Fry DW, et al.: Tyrosine kinase inhibitors.7.7-amino-4-(phenylamino)-and7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines:a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factorreceptor. J Med Chem,1995,38:3780-3788.
[94] Rewcastle GF, Palmer BD, Thompson AM, et al.: Tyrosine kinase inhibitors.10. Isomeric4-[(3-bromophenyl)amino]pyrido[d]pyrimidines are potent ATP binding site inhibitors ofthe tyrosine kinase function of the epidermal growth factor receptor. J Med Chem,1996,39:1823-1835.
[95] Rewcastle GW, Murray DK, Elliott WL, et al.: Tyrosine kinase inhibitors.14.Structure-activity relationships for methyl-amino-substituted derivatives of4-[(3-bromophenyl)amino]-6(methylamino)-pyrido[3,4-d]pyr-imidine (PD158780), apotent and speci c inhibitor of the tyrosine kinase activity of receptors for the EGF familyof growth factor. J Med Chem,1998,41:742-751.
[96] Thompson AM, Murray DK, Elliott WL, et al.: J Med Chem,1997,40:3915-3925.
[97] Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA. J MedChem1997;40:1519.
[98] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802438;1998.
[99] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802437;1998.
[100] Cockerill GS, Guntrip SB, McKeown SK, et al., inventors. Glaxo Group WO-09713771;1997.
[101] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-19629652-A1;1998.
[102] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-1960831-A1;1997.
[103] Blankley CJ, Boschelli DH, Doherty AM, et al. Warner Lambert WO-09634867;1996.
[104] Connolly CJC, Hamby JM, Schroeder MC, et al.: Discovery and structure-activity studiesof a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. Bioorg Med ChemLett,1997,7:2415-2418.
[105] Hamby JM, Connolly CJ, Schroeder MC, et al.: Structure-activity relationships for a novelseries of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem,1997,40:2296-2303.
[106] Mohammadi M, Froum S, Hamby JM, et al.: Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain. EMBO J,1998,17:5896-5904.
[107] Panek RL, Lu GH, Klutchko SR, et al.: a new nanomolar potent and broadly active proteinkinase inhibitor. J Pharmacol Exp Ther,1997,283:1433-1444.
[108] Boschelli DH, Wu Z, Klutchko SR, et al.: synthesis and tyrosine kinase inhibitory activityof a series of2-amino-8H-pyrido[2,3-d]pyrimidines: identigication of potent, selectiveplatelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem,1998,41:4365-4377.
[109] Rewcastle GF, Bridges AJ, Fry DW, et al.: Tyrosine Kinase Inhibitors.12. Synthesis andStructure-Activity Relationships for6-Substituted4-(Phenylamino) pyrimido[5,4-d]pyrimidines Designed as Inhibitors of the Epidermal Growth Factor Receptor. J MedChem,1997,40:1820-1826.
[110] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae WO-09732880;1997.
[111] Himmelsbach F, Dahmann G, von Ruden T, et al. WO-09732882;1997.
[112] Traxler P, Bold G, Buchdunger E, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[113] Missbach M, Jeschke M, Field JB, et al.: A novel inhibitor of the tyrosine kinase Srcsuppresses phosphorylation of its major cellular substrates and reduces bone resorption invitro and in rodent models in vivo. Bone,1999,24:437-449.
[114] Missbach M, Green J, Susa M, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[115] Altmann E, inventor. Novartis AG WO-09734895;1997.
[116] Altmann E, Missbach M, Widler L. Novartis AG WO-09732879;1997.
[117] Altmann E, Missbach M, Widler L, et al. Novartis AG WO-09749706;1997.
[118] Altmann E, Widler L, Missbach M. Novartis AG WO-09728161;1997.
[119] Missbach M. Ciba–Geigy WO-09610028;1996.
[120] Henry JR, Rupert KC, Dodd JH, et al.:6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (RWJ68354): A Potent and Selective p38KinaseInhibitor J Med Chem,1998,41:4196-4198.
[121] Hanke JH, Gardner JP, Dow RL, et al.: Discovery of a novel, potent, and Srcfamily-selective tyrosine kinase Inhibitor: study of Lck-and FynT-dependent T cellactivation. J Biol Chem,1996,271:695-701.
[122] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651-661.
[123] Bishop AC, Kung CY, Shah K, et al.: Generation of monospecific nanomolar tyrosinekinase inhibitors via a chemical genetic approach. J Am Chem Soc,1999,121:627-631.
[124] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814451;1998.
[125] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814449;1998.
[126] Tang PC, Sun L, McMahon G, et al. Sugen WO-09850356;1998.
[127] Tang C, Sun L, McMahon G, et al. Sugen WO-09807695;1998.
[128] Sun L, Tran F, App H, et al.: Synthesis and biological evaluations of3-substitutedindolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity towardparticular receptor tyrosine kinases. J Med Chem,1998,41:2588-2603.
[129] Battistini C, Ermoli A, Vioglio S, et al. Pharmacia&Upjohn WO-09745409;1997.
[130] Battistini C, Vioglio S, Buzzetti F, et al. Pharmacia&Upjohn WO-09746551;1997.
[131] McNutt RW, Jung DK, Harris PA, et al., inventors. Glaxo Group WO-09910325;1999.
[132] Lackey K, Chapman D, Crosby RM, et al. Proc Am Assoc Cancer Res1999;40:124.
[133] Davis ST, Dickerson SH, Frye SV, et al. Glaxo Group WO-09915500;1999.
[134] Luzzio MJ, Bramson N, Dickerson S, et al. Proc Am Assoc Cancer Res,1999,40:622.
[135] Parker CW, Entsch B, Letham DS. Inhibitors of cytokinin metabolism I. Inhibition of twoenzymes which metabo-lize cytokinins. Phytochem,1986,25:303-310.
[136] Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol,1996,6:393-397.
[137] Vesely J, Havlicek L, Strnad M, et al. Progress in Cell Cycle Research. Eur J Biochem1994,224:771-786.
[138] MacCallum DE, Melville J, Frame S, et al.: Seliciclib (CYC202, R-Roscovitine) inducescell death in multi-ple myeloma cells by inhibition of RNA polymerase II-dependenttranscription and down-regulation of Mcl-1Cancer Research,2005,65(12):5399–5407.
[139] Noopur Raje, Shaji Kumar, Teru Hideshima, et al.: Seliciclib (CYC202or R-roscovitine), asmall-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulationofMcl-1in multiple myeloma. Blood,2005,106(3):1042–1047.
[140] Rossi AG, Sawatzky DA, Walker A, et al.: Cyclin-dependent kinase inhibitors enhance theresolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine,2006,12(9):1056–1064.
[141] Gray NS, Wodicka L, Thunnissen AMWH, et al.: Exploiting chemical libraries, structure,and genomics in the search for kinase inhibitors. Science,1998,281:533-538.
[142] Imbach P, Capraro HG, Furet P, et al.:2,6,9-trisubstituted purines: optimization towardshighly potent and selective CDK1inhibitors. Bioorg Med Chem Lett,1999,9:91-96.
[143] Adams JL, Boehm JC, Kassis S, et al.: Pyrimidinylimidazole inhibitors of CSBP/p38kinase demonstrating decreased inhibition of hepatic cytochrome P450enzymes. BioorgMed Chem Lett,1998,8:3111-3116.
[144] Jackson JR, Bolognese B, Hillegass L, et al.: Pharmacological Effects of SB220025, aSelective Inhibitor of P38Mitogen-Activated Protein Kinase, in Angiogenesis and ChronicInflammatory Disease Models. J Pharmacol Exp Ther,1998,284:687-692.
[145] Frantz B, Klatt T, Pang M, et al.: Induction of apoptosis by SB202190through inhibitionof p38β mitogen-activated protein kinase. Biochem,1998,37:13846-13853.
[146] Liverton NJ, Butcher JW, Clairbone CF, et al.: Design and Synthesis of Potent, Selective,and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38Mitogen-ActivatedProtein Kinase. J Med Chem,1999,42:2180-2190.
[147] Heimbrook DC, Huber HE, Stirdivant SM, et al.: Epidermal growth factor induction of thec-jun promoter by a Rac pathway. Proc Am Assoc Cancer Res,1998,39:558-559.
[148] Meyer T, Regenass U, Fabbro D, et al.: A derivative of staurosporine (CGP41251) showsselectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivoanti-tumor activity. Int J Cancer,1989,43:85-856.
[149] Mehta AB, Virchis AE, Jones DT, et al.: The formation of new blood vessels from anexisting vascular network. Blood,1997,90:3634-3641.
[150] P. A. Campochiaro and the C99-PKC412-003Study Group, Invest. Ophthalmol. VisualSci.,2004,45:922–931.
[151] Takahashi I, Kobayashi E, Asano K, et al. UCN-01, a selective inhibitor of protein kinaseC from Streptomyces. J Antibiot,1987,40:1782-1784.
[152] Akinaga S, Sugiyama K, Akiyama T. UCN-01(7-hydroxystaurosporine) and otherindolocarbazole compounds: a new generation of anti-cancer agents for the new century?.Anti-Cancer Drug Des,2000,15:43–52.
[153] K. Grosios, UCN-01Kyowa Hakko Kogyo Co. Curr. Opin. Invest. Drugs (Thomson Sci.),2001,2:287–297.
[154] Senderowicz AM. The Cell Cycle as a Target for Cancer Therapy: Basic and ClinicalFindings with the Small Molecule Inhibitors Flavopiridol and UCN-01. Oncologist,2002,7(suppl.3),12–19.
[155] Butler MS. Natural products to drugs: natural product derived compounds in clinical trials.Nat. Prod. Rep.,2005,22:162–195.
[156] ClinicalTrials.gov (a service of the US National Institutes of Health). Available athttp://clinicaltrials.gov.
[157] Fuse E, Kuwabara T, Sparreboom A, et al.: Review of UCN-01development: a lesson inthe importance of clinical pharmacology. J. Clin. Pharmacol,2005,45:394–403.
[158] Sausville EA. Indifferently Pursued or Unowned Drugs: Who Should Lead WhereCompanies Do Not Tread?. J. Clin. Oncol,2005,23:1796–1798.
[159] Camoratto AM, Jani J P, Angeles TS, et al.: CEP-751inhibits trk receptor tyrosine kinaseactivity in vitro and exhibits anti-tumor activity. Int. J. Cancer,1997,72:673–679.
[160] Ruggeri BA, Miknyoczki SJ, Singh J, et al.: Role of neurotrophin–trk interactions inoncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors inpre-clinical tumor models. Curr. Med. Chem.,1999,6:845–857.
[161] Strock CJ, Park JI, Rosen DM, et al.: Activity of irinotecan and the tyrosine kinaseinhibitor CEP-751in medullary thyroid cancer. J Clin Endocrinol Metab. J. Clin.Endocrinol. Metab.,2006,91:79–84.
[162] Strock CJ, Park JI, Rosen M, et al.: Activated RET Tyrosine Kinase Activity and BlockMedullary Thyroid Carcinoma Cell Growth. Cancer Res.,2003,63:5559–5563.
[163] Brown P, Levis M, McIntyre E, et al.: Constitutively activated FLT3phosphorylates BADpartially through pim-1. Leukemia,2006,20:1368–1376.
[164] Smith BD, Levis M, Beran M, et al.: Single Agent CEP-701, a novel FLT3inhibitor, showsbiologic response and clinical activity in patients with relapsed or refractory acute myeloidleukemia. Blood,2004,103:3669–3676.
[165] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solidtumors. Invest. New Drugs,2004,22:449–458.
[166] Camoratto AM, Jani JP, Angeles T, Maroney A, et al.: CEP-751inhibits trk receptortyrosine kinase activity in vitro and exhibits anti-tumor activity. Int J Cancer,1997,72:673-679.
[167] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solidtumors. Invest. New Drugs,2004,22:449–458.
[168] Gingrich DE, Reddy DR, Iqbal MA, et al.: A New Class of Potent Vascular EndothelialGrowth Factor Receptor Tyrosine Kinase Inhibitors: Structure Activity Relationships fora Series of9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo [3,4-c]carbazole-5-ones and the Identification of CEP-5214and Its Dimethylglycine Ester Prodrug ClinicalCandidate CEP-7055. J. Med. Chem.,2003,46:5375–5388.
[169] Jirousek MR, Gillig JR, Gonzalez CM, et al.:(S)-13-[(Dimethylamino)methyl]-10,11,14,15–tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues: Isozyme SelectiveInhibitors of Protein Kinase Cβ. J. Med. Chem.,1996,39:2664–2671.
[170] Tuttle KR, Bakris GL, Toto RD, et al.: The Effect of Ruboxistaurin on Nephropathy inType2Diabetes. Diabetes Care,2005,28:2686–2690.
[171] Vinik AI, Bril V, Kempler P, et al.: Treatment of symptomatic diabetic peripheralneuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a1-year,randomized, placebo-controlled, double-blind clinical trial. Clin. Ther.,2005,27:1164–1180.
[172] Aiello LP, Clermont A, Arora V, et al.: Inhibition of PKC β by Oral Administration ofRuboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal HemodynamicAbnormalities in Patients. Invest. Ophthalmol. Visual Sci.,2006,47:86–92.
[173] Faul MM, Gillig JR, Jirousek MR, et al.: Acyclic N-(azacycloalkyl)bisindolylmaleimides:Isozyme Selective Inhibitors of PKC. Bioorganic&Medicinal Chemistry Letters,2003,13:1857–1859.
[174] Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain ofc-Abl in complex with the small molecule inhibitors PD173955and imatinib (STI-571).Cancer Res.2002,62:4236–4243.
[175] Hancock, C.N. et al. Identification of novel extracellular signal-regulated kinase dockingdomain inhibitors. J. Med. Chem.2005,48:4586–4595.
[176] Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design:a molecular modeling perspective. Med Res Rev.,1996,16:3–50.
[177] Hann MM, Oprea TI. Pursuing the leadlikeness concept in pharma-ceutical research. CurrOpin Chem Biol.2004,8:255–263.
[178] Fink T, Bruggesser H, Reymond JL. Virtual exploration of the small-molecule chemicaluniverse below160daltons. Angew Chem Int Ed Engl.2005,44:1504–1508.
[179] Kolb HC, Sharpless KB. The growing impact of click chemistry on drug discovery. DrugDiscovery Today,2003,8,1128–1137.
[180] Whiting M, Tripp JC, Lin YC, et al.: Rapid Discovery and Structure Activity Profiling ofNovel Inhibitors of Human Immunodeficiency Virus Type1Protease Enabled by theCopper(I)-Catalyzed Synthesis of1,2,3-Triazoles and their further functionalization. J.Med.Chem.,2006,49,7697–7710.
[1] Relles. Organic chemistry in thionyl chloride. I. Dichloromaleimide chemistry. II. Thionylchloride-pyridine method for the conversion of maleimides to dichloromaleimides. HowardM. J. Org. Chem.1972,37:3630-3637.
[2] Margaret M. Faul, Kevin A. Sullivan, Leonard L. Winneroski, A geneal approach to thesynthesis of Bisindolymaleimides: Synthesis of Staurosporine Aglycone. Synthesis,1995,12:1511-1516.
[3] J. Bain, H. McLauchlan, M. Elliott and P. Cohen, Biochem. J.,2003,371:199-204.
[4] R. Li and J. A. Staford, Kinase inhibitor drugs, Wiley, Hoboken, NJ,2009.
[5] Noble ME, Endicott JA, Johnson LN. Protein Kinase Inhibitors: Insights into Drug Designfrom Structure. Science,2004,303,1800.
[1] Min Wang, Mingzhang Gao, Kathy DM, et al.: The first syntheseis of [11C]SB-216763, anew potential PET agent for imaging of glycogen synthase kinase-3(GSK-3). Bioorganic&Medicinal Chemistry Letters.2011,21,245-249.
[2] Terry VH and Michael PC. Total synthesis of Didemnimide A and B. Tetrahedron Letters.1998,39,9629-9630.
[3] Trost BM, Xie Jia, Sieber JD. The palladium catalyzed asymmetric addition of oxindoles andallenes: An atom-economical versatile method for the construction of chiral indole alkaloids.Journal of American Chemical Society,2011,133,20611-20622.
[1] Gill M, Steglich W, in Progress in the Chemistry of Organic Natural Products, ed. W. Herz, H.Grisebach, G. W. Kirby and C. Tamm, Springer-Verlag, New York,1987, vol.51, pp.1–317.
[2] W. Steglich, Pure Appl. Chem.,1989,61,281–288.
[3] Bergman J, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman, Elsevier,Amsterdam,1988, vol.1(Stereoselective synthesis, Part A), pp.3–30.
[4] Bergman J., Janosik T. and N.Wahlstrom, in Advances in Heterocyclic Chemistry, ed. A.Katritzky, Academic Press, New York,2001, vol.80, pp.1–71.
[5] Gribble GW, Berthel SJ, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman,Elsevier, Amsterdam,1993, vol.12(Stereoselective synthesis, Part H), pp.365–409.
[6] M. Prudhomme, Curr. Pharm. Des.,1997,3,265–290.
[7] M. Prudhomme, Curr. Med. Chem.,2000,7,1189–1212.
[8] M. Prudhomme, Eur. J. Med. Chem.,2003,38,123–140.
[9] Pindur U, Kim YS, Mehrabani F, Curr. Med. Chem.,1999,6,29–69.
[10] Knolker HJ, Reddy KR, Chem. Rev.,2002,102,4303–4427.
[11] Long BH, Rose WC, Vyas DM, et al.: Curr. Med. Chem.: Anti-Cancer Agents,2002,2,255–266.
[12] Kawasaki T, Higuchi K, Nat. Prod. Rep.,2005,22,761–793.
[13] anchez CS′, endez CM′, Salas JA, J. Ind. Microbiol. Biotechnol.,2006,33,560–568.
[14] Omura S, Iwai Y, Hirano A,et al.:, J. Antibiot.,1977,30,275–282.
[15] Funato N, Takayanagi H, Konda Y, et al.: Tetrahedron Lett.,1994,35,1251–1254.
[16] Link JT, Raghavan S, Gallant M, et al.: J. Am. Chem. Soc.,1996,118,2825–2842.
[17] Butler MS, Nat. Prod. Rep.,2005,22,162.
[18] Meksuriyen D, Cordell GA, J. Nat. Prod.,1988,51,893–899.
[19] Yang SW, Cordell GA, J. Nat. Prod.,1996,59,828–833.
[20] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,788–790.
[21] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,236–241.
[22] Yang SW, Lin LJ, Cordell GA, et al. J. Nat. Prod.,1999,62,1551–1553.
[24] Pearce CJ, Doyle TW, Forenza S, et al. J. Nat. Prod.,1988,51,937–940.
[23] Onaka H, Taniguchi S, Igarashi Y, et al. J. Antibiot.,2002,55,1063–1071.
[24] Anchez CS, Zhu L, Bra na AF, et al. Proc. Natl. Acad. Sci. U. S. A.,2005,102,461–466.
[25] Salas AP, Zhu L, Sáanchez C, et al. Mol. Microbiol.,2005,58,17–27.
[26](a) Liu J and Gin DY, J. Am. Chem. Soc.,2002,124,9789;(b) Honda E and Gin DY, J. Am.Chem. Soc.,2002,124,7343;(c) Tiwari P and Misra AK, J. Org. Chem.,2006,71,2911.
[27](a) Jayakanthan K and Vankar YD, Org. Lett.,2005,7,5441;(b) Saeeng R and Isobe M,Org. Lett.,2005,7,1585;(c) Lehmann U, Awasthi S and Minehan T, Org. Lett.,2003,5,2405;(d) V. Di Bussolo, M. Caselli, M. Pineschi, et al. Org. Lett.,2003,5,2173.
[28](a) Yin J, Spindler J andLinker T, Chem. Commun.,2007,2712;(b) Larrosa I, Romea P, UrpF, et al. Org. Lett.,2002,4,4651;(c) Parrish JD andLittle RD, Org. Lett.,2002,4,1439;(d)Rainier JD andCox JM, Org. Lett.,2000,2,2707;(e) Thorn SN and Gallagher T, Synlett,1996,856.
[29](a) Boulineau FP andWei A, Org. Lett.,2004,6,119;(b) Seeberger PH, Eckhardt M,Gutteridge CE, et al, J. Am. Chem. Soc.,1997,119,10064.
[30](a) Dahl RS and Finney NS, J. Am. Chem. Soc.,2004,126,8356;(b). Colinas PA and BravoRD, Org. Lett.,2003,5,4509;(c) Li BQ, Franck RW, Capozzi G, et al. Org. Lett.,1999,1,111.
[31](a) Cousins GS and Hoberg JO, Chem. Soc. Rev.,2000,29,165;(b) Haveli SD, Sridhar PR,Suguna P, et al. Org. Lett.,2007,9,1331.
[32](a) DiBussolo V, Romano MR, Pineschi M, et al. Org. Lett.,2005,7,1299;(b) Kim JY,Bussolo VD, Gin DY. Org. Lett.,2001,3,303.
[33](a) Roush WR andBennett CE, J. Am. Chem. Soc.,1999,121,3541;(b) DiBussolo V, KimY J, Gin DY, J. Am. Chem. Soc.,1998,120,13515.
[34] Lemieux RU and Ratcliffe RM, Can. J. Chem.,1979,57,1244.
[35] Roth W, Pigman W. Methods Carbohydr. Chem.1963,2,405–408.
[36] Eitelman SJ. Jordaan A. J. Chem. Soc., Chem. Commun.1977,552–553.
[37] Ireland RE, Wilcox CS, Thaisrivongs S. J. Org. Chem.1978,43,786–787.
[38] Spencer RP, Cavallaro CL, Schwartz J. J. Org. Chem.1999,64,3987–3995.
[39]Cavallaro CL, Schwart J. J. Org. Chem.1995,60,7055–7057.
[40] Hansen T, Daasbjerg K, Skrydstrup T. Tetrahedron Lett.2000,41,8645–8649.
[41] Kovács G, Micskei K, Somsák L. Carbohydr. Res.2001,336,225–228.
[42] Pollon, J. H. P.; Llewellyn, G.; Williams, J. M. Synthesis1989,758–759.
[43] Fürstner, A.; Weidmann, H. J. Carbohydr. Chem.1988,7,773–783.
[44] Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth. Commun.1992,22,2459–2477.
[45] Forbes, C. L.; Franck, R. W. J. Org. Chem.1999,64,1424–1425.
[46] Boutureira, O.; Rodríguez, M. A.; Matheu, M. I.; Díaz, Y.; Castillón, S. Org. Lett.2006,8,673–675.
[47] Micskei, K.; Juhász, Z.; Ratkovic, Z. R.; Somsák, L. Tetrahedron Lett.2006,47,6117–6120.
[48] Gómez, A. M.; Casillas, M.; Barrio, A.; Gawel, A.; López, J. C. Eur. J. Org. Chem.2008,3933–3942.
[49] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Green Chem.,2009,11,1124–1127.
[50] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Carbohydrate Research.2010,345,168–171.
[51] Subramaniam Sabesan and Susana Neira J. Org. Chem.,1991,56(18),5468-5472.
[52] Guisheng Zhang, Jie Shen, Hao Cheng, Lizhi Zhu, Lanyan Fang, Sanzhong Luo, Mark T.Muller, Gun Eui Lee, Lijun Wei, Yuguo Du, Duxin Sun, and Peng George Wang. J. Med.Chem.2005,48,2600-2611.
[53] César Sánchez, Aaroa P. Salas, Alfredo F. Bra a, et al. Chem. Commun.,2009,4118-4120.
[54] Yang M, Zhou J, Schneller SW. Tetrahedron2006,62,1295.
[55] Michel BY, Strazewski P. Tetrahedron2007,63,9836.
[56] Kumara Swamy KC, Bhuvan Kumar NN, Balaraman E, et al. Chem. Rev.2009,109,2551–2651.
[1] Wang M, Xu L, Gao MZ, et al.: Enzastaruin, the first design and radiosynthesis of a newpotential PET agent for imaging of protein kinase C. Bioorganic&Medicinal Chemistry letters.2011,21:1649-1653.
[2] Bradford VW, Radhakrishnan U, Joshua C, et al. WO2006020879.
[1] Nishzuka Y: Intracellular signaling by hydrolysis of phospholipid and activation of proteinkinase C. Science1992,258:607–614.
[2] Edelman A, Blumenthal D, Krebs E: Protein serine/threonine kinases. Annu Rev Biochem1987,56:567–613.
[3] Fantl W, Johnson, D, Williams LT: Signaling by receptor tyrosine kinases. Annu RevBiochem1993,62:453–481.
[4] Yarden Y, Ulrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem1988,57:443–478.
[5] Manning G, Whyte DB, Martinez R, et al.: The protein kinase complement of the humangenome. Science,2002,298:1912–1234.
[6] Cohen P: The role of protein phosphorylation in human health and disease. Eur J Biochem2001,268:5001–5010.
[7] G. Burnett, and E. P. Kennedy, The enzymatic phosphorylation of proteins. J Biol Chem1954,211:969–980.
[8] Uckun F, Mao C: Tyrosine kinases as new molecular targets in treatment of inflammatorydisorders and leukemia. Curr Pharm Des,2004,10:1083–1091.
[9] Knuutila S, Bjorkqvist AM, Autio K, Tarkkaqnen M, Wolf M, Monni O, et al.: DNA copynumber amplifications in human neoplasms: review of comparative genomic hybridizationstudies. Am J Pathol,1998,152:1107–1123.
[10] Noble M, Endicott J, Johnson L: Protein kinase inhibitors: insights into drug design fromstructure. Science,2004,303:1800–1805.
[11] Dancy J, Sausville EA: Issues and progress with protein kinase inhibitors for cancertreatment. Nat Rev Drug Discov,2003,2:296–313.
[12] DiGiovanna MP, Stern DF, Edgerton SM, et al.: Relationship of epidermal growth factorreceptor expression to ErbB-2signaling activity and prognosis in breast cancer patients. J ClinOncol,2005,23:1152–1160.
[13] Piccart-Gebhart M, Procter M, Leyland-Jones B, et al.: Herceptin Adjuvant (HERA) TrialStudy Team. N Engl J Med,2005,353:1659-1672.
[14] Druker B, Tamura S, Buchdunger E, et al.: Effects of a selective inhibitor of the Abl tyrosinekinase on the growth of Bcr-Abl positive cells. Nat Med,1996,2:561–566.
[15] Druker B, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of theBCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med,2001,344:1031–1037.
[16] Barker AJ, Gibson KH, Grundy W, et al.: Studies leading to the identification of ZD1839(IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitortargeted to the treatment of cancer. Bioorg Med Chem Lett,2001,11:1911–1914.
[17] Karaman M, Herrgard S, Treiber D, et al.: A quantitative analysis of kinase inhibitorselectivity. Nat Biotechnol,2008,26:127–132.
[18] Druker BJ: STI571(Gleevec) as a paradigm for cancer therapy. Trends Mol Med,2002,8(Suppl): S14–S18.
[19] Sawyer T: Novel oncogenic protein kinase inhibitors for cancer therapy. Curr Med ChemAnti-Cancer Agents,2004,4:449–455.
[20] E Ter Haar, WP Walters, S Pazhanisamy, P Taslimi, AC Pierce, GW Bemis, et al.: Kinasechemogenomics: targeting the human kinome for target validation and drug discovery. Mini RevMed Chem,2004,4:235–253.
[21] Nagar B, Bornmann WG, Pellicena P, et al.: Crystal structures of the kinase domain of c-Ablin complex with the small molecule inhibitors PD173955and imatinib (STI-571). Cancer Res,2002,62:4236–4243.
[22] Corbin A, La Rosee P, Stoffregen E, et al.: Several Bcr-Abl kinase domain mutantsassociated with imatinib mesylate resistance remain sensitive to imatinib. Blood,2003,10:4611–4614.
[23] Gorre M, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571cancer therapycaused by BCR-ABL gene mutation or amplification. Science,2001,293:876–880.
[24] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651–661.
[25] Walker E, Pacold M, Perisic O, et al.: Structural determinants of phosphoinositide3-kinaseinhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell,2000,6:909–919.
[26] Tong L, Pav S, White D, Rogers S, et al.: A highly specific inhibitor of human p38MAPkinase binds in the ATP pocket. Nat Struct Biol,1997,4:311–316.
[27] Fitzgerald C, Patel S, Becker J, et al.: Structural basis for p38alpha MAP kinasequinazolinone and pyridol-pyrimi-dine inhibitor specificity. Nat Struct Biol,2003,10:764–769.
[28] Shen G: Selective protein kinase C inhibitors and their applications. Curr Drug TargetsCardiovasc Haematol Disord,2003,3:301–307.
[29] Kim C, Xuong NH, Taylor SS: Crystal structure of a complex between the catalytic andregulatory (RIalpha) subunits of PKA. Science,2005,307:690–696.
[30] Karin M, Yamamoto Y, Wang Q: The IKK NF-kappa B system: a treasure trove for drugdevelopment. Nat Rev Drug Discov,2004,3:17–26.
[31] May M, Ghosh S: IκB kinases: kinsmen with different crafts. Science,1999,284:271-273.
[32] Barnes PJ, Karin M: Nuclear factor-kappaB: a pivotal transcription factor in chronicinflammatory diseases. N Engl J Med,1997,336:1066–1071.
[33] Haefner B: NF-kappa B: arresting a major culprit in cancer. Drug Discov Today,2002,7:653–663.
[34] Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol,2002,3:221–227.
[35] May M, D’Acquisto F, Madge L, et al.: Selective inhibition of NFkB activation by a peptidethat blocks the interaction of NEMO with the IkB kinase complex. Science,2000,289:1550–1554.
[36] Pallàs M, Verdaguer E, Jordà EG, et al.: Flavopiridol: an antitumor drug with potentialapplication in the treatment of neurodegenerative diseases. Med Hypoth,2005,64:120–123.
[37] Knockaert M, Greengard P, Meijer L: Pharmacological inhibitors of cyclin-dependentkinases. Trends Pharmacol Sci,2002,23:417–425.
[38] Pavletich NP: Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, theircyclin activators, and Cip and INK4inhibitors. J Mol Biol,1999,287:821–828.
[39] Stevenson LM, Deal MS, Hagopian JC, et al.: Activation mechanism of CDK2: role ofcyclin binding versus phosphorylation. Biochemistry,2002,41:8528-8534.
[40] Hirai H, Kawanishi N, Iwasawa Y: Recent advances in the development of selective smallmolecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem,2005,5:167–179.
[41] Jeffrey P, Tong L, Pavletich N: Structural basis of inhibition of CDK-cyclin complexes byINK4inhibitors. Genes Dev,2000,14:3115–3125.
[42] Roy KK, Sausville E: Early development of cyclin dependent kinase modulators. CurrPharm Des,2001,7:1669–1687.
[43] Parry D, Bates S, Mann DJ, et al.: Lack of cyclin D-Cdk complexes in Rb-negative cellscorrelates with high levels of p16INK4/MTS1tumour suppressor gene product. EMBO J,1995,14:503–511.
[44] Hall M, Peters G: Genetic alterations of cyclins, cyclin-dependent kinases, and Cdkinhibitors in human cancer. Adv Cancer Res,1996,68:67–108.
[45] Zuo L, Weger J, Yang Q, et al.: Germline mutations in the p16INK4a binding domain ofCDK4in familial melanoma. Nat Genet,1996,12:97–99.
[46] Ghosh S, Liu X, Zheng Y, et al.: Rational design of potent and selective EGFR tyrosinekinase inhibitors as anticancer agents. Curr Cancer Drug Targets,2001,1:129–140.
[47] Wehrman TS, Raab WJ, Casipit CL, et al.: A system for quantifying dynamic proteininteractions defines a role for Herceptin in modulating ErbB2interactions. Proc Natl Acad SciUS,2006,103:19063–19068.
[48] Schlessinger J, Ullrich A: Growth factor signaling by receptor tyrosine kinases. Neuron1992,9:383–391.
[49] Zhu H, Iaria J, Orchard S, et al.: Epidermal growth factor receptor: association ofextracellular domain negatively regulates intracellular kinase activation in the absence of ligand.Growth Factors,2003,21:15–30.
[50] Boldt S, Kolch W: Targeting MAPK signalling: Prometheus’ fire or Pandora’s box? CurrPharm Des,2004,10:1885–1905.
[51] Kumar S, Boehm J, Lee J: p38MAP kinases: key signalling molecules as therapeutic targetsfor inflammatory diseases. Nat Rev Drug Discov,2003,2:717–726.
[52] Sebolt-Leopold J, Herrera R: Targeting the mitogen-activated protein kinase cascade to treatcancer. Nat Rev Cancer,2004,4:937–947.
[53] Pearson G, Robinson F, Beers Gibson T, et al.: Mitogen-activated protein (MAP) kinasepathways: regulation and physiological functions. Endocr Rev,2001,22:153–183.
[54] Marshall C: How do small GTPase signal transduction pathways regulate cell cycle entry?Curr Opin Cell Biol,1999,11:732–736.
[55] McMahon M, Woods D: Regulation of the p53pathway by Ras, the plot thickens. BiochimBiophys Acta,2001,1471: M63–M71.
[56] Gupta S, Barrett T, Whitmarsh AJ, et al.: Selective interaction of JNK protein kinaseisoforms with transcription factors. EMBO J,1996,15:2760–2770.
[57] Manning A, Davis R: Targeting JNK for therapeutic benefit: from junk to gold? Nat DrugDiscov,2003,2:554–565.
[58] Manning AM, Mercurio F: Transcription inhibitors in inflammation. Expert Opin InvestigDrugs,1997,6:555–567.
[59] Bennett BL, Sasaki DT, Murray BW, et al.: SP600125, an anthrapyrazolone inhibitor of JunN-terminal kinase. Proc Natl Acad Sci USA,2001,98:13681–13686.
[60] Han Z, Boyle DL, Chang L, et al.: c-Jun N-terminal kinase is required for metalloproteinaseexpression and joint destruction in inflammatory arthritis. J Clin Invest,2001,108:73–81.
[61] Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulinresistance. Nature,2002,420:333–336.
[62] Adams JL, Badger AM, Kumar S, et al: p38MAP kinase: molecular target for the inhibitionof pro-inflammatory cytokines. Prog Med Chem,2001,38:1–60.
[63] Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov2003,2:473–488.
[64] Badger AM, Bradbeer J, Votta B, et al: Pharmacological profile of SB203580, a selectiveinhibitor of cytokine suppressive binding protein/p38kinase, in animal models of arthritis, boneresorption, endotoxin shock and immune function. J Pharmacol Exp Ther,1996,279:1453–1461.
[65] Regan J, Breitfelder S, Cirillo P, et al.: Pyrazole urea-based inhibitors of p38MAP kinase:from lead compound to clinical candidate. J Med Chem,2002,45:2994–3008.
[66] Badger AM, Griswold DE, Kapadia R, et al.: Disease-modifying activity of SB242235, aselective inhibitor of p38mitogen-activated protein kinase, in rat adjuvant-induced arthritis.Arthritis Rheum,2000,43:175–183.
[67] Mclay LM, Halley F, Souness JE, et al.: The discovery of RPR200765A, a p38MAP kinaseinhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem,2001,9:537–554.
[68] Ma XL, Kumar S, Gao F, et al.: Inhibition of p38mitogen-activated protein kinase decreasescardiomyocyte apoptosis and improves cardiac function after myocardial ischemia andreperfusion. Circulation,1999,99:1685–1691.
[69] Gutkind JS: The pathways connecting G protein coupled receptors to the nucleus throughdivergent MAPK’s. J Biol Chem,1998,273:1839–1842.
[70] Wen D, Nong Y, Morgan JG, et al.: A selective small molecule IkappaB Kinase betainhibitor blocks nuclear factor kappaB-mediated inflammatory responses in humanfibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther,2006,317:989–1001.
[71] Palanki MS, Gayo-Fun L, Shevlin G, et al.: Structure-activity relationship studies of ethyl2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: aninhibitor of AP-1and NF-kappaB mediated gene expression. Bioorg Med Chem Lett,2002,12:2573–2577.
[72] Castro AC, Dang L, Soucy F, et al.: Novel IKK inhibitors: beta-carbolines. Bioorg MedChem Lett,2003,13:2419–2422.
[73] Burke JR, Pattoli MA, Gregor KR, al.: BMS-345541is a highly selective inhibitor of Ikappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependenttranscription in mice. J Biol Chem,2003,278:1450–1456.
[74] Bhat R, Budd S, Haeberlein L, et al: Glycogen synthase kinase3: a drug target for CNStherapies. J Neurochem,2004,89:1313–1317.
[75] Murphy E: Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest,2004,113:1526–1528.
[76] Coghlan MP, Culbert AA, Cross DA, et al.: Selective small molecule inhibitors of glycogensynthase kinase-3modulate glycogen metabolism and gene transcription. Chem Biol,2000,7:793–803.
[77] Mussmann R, Geese M, Harder F, et al.: Inhibition of GSK3promotes replication andsurvival of pancreatic beta cells. J Biol Chem,2007,282:12030-12037.
[78] Lucas J, Hernandez F, Gomez-Ramos P, et al.: Decreased nuclear beta-catenin, tauhyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBOJ,2001,20:27-39.
[79] Rondinone CM: Diabetes: the latest developments in inhibitors, insulin sensitisers, new drugtargets and novel approaches. October18-19,2004, The Hatton, London, UK. Expert Opin TherTargets,2005,9,415-418.
[80] Leal EC, Santiago AR, Ambrósio AF: Old and new drug targets in diabetic retinopathy:from biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNSNeurol Disord,2005,4:421–434.
[81] Beckman JA, Goldfine AB, Gordon MB, et al.: Inhibition of protein kinase Cbeta preventsimpaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res,2002,90:107–111.
[82] Meier M, King GL: Protein kinase C activation and its pharmacological inhibition invascular disease. Vasc Med,2000,5:173–185.
[83] Frank RN: Potential new medical therapies for diabetic retinopathy: protein kinase Cinhibitors. Am J Ophthalmol,2002,133:693–698.
[84] Kunkel MW, Hook KE, Howard CT, et al.: Inhibition of the epidermal growth factorreceptor tyrosine kinase by PD153035in human A431tumors in athymic nude mice. Invest NewDrug,1996,13:295-302.
[85] Woodburn JR, Barker AJ, Gibson KH, et al.: ZD1839, an epidermal growth factor tyrosinekinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res,1997,38:633-634.
[86] Zimmermann J, Buchdunger E, Mett H, et al.: Potent and selective inhibitors of the Ablkinase-phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett,1997,7:187-192.
[87] Zimmermann J, Buchdunger E, Mett H, et al.: Phenylamino-pyrimidine (PAP)-derivatives: anew class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. BioorgMed Chem Lett,1996,6:1221-1226.
[88] Zimmermann J, Caravatti G, Mett H, et al.: a new class of potent and selective inhibitors ofprotein kinase C. Arch Pharm Weinheim,1996,329:371-376.
[89] Thomas AP, inventor. Zeneca WO-09515952;1995.
[90] Davis PD, Moffat DFC, Davis JM, et al. Celltech Therapeutics WO-09719065;1997.
[91] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519774;1995.
[92] Bridges AJ, Denny WA, Fry DW, et al. Warner Lambert WO-09519970;1995.
[93] Thompson AM, Bridges AJ, Fry DW, et al.: Tyrosine kinase inhibitors.7.7-amino-4-(phenylamino)-and7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines: anew class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. JMed Chem,1995,38:3780-3788.
[94] Rewcastle GF, Palmer BD, Thompson AM, et al.: Tyrosine kinase inhibitors.10. Isomeric4-[(3-bromophenyl)amino]pyrido[d]pyrimidines are potent ATP binding site inhibitors of thetyrosine kinase function of the epidermal growth factor receptor. J Med Chem,1996,39:1823-1835.
[95] Rewcastle GW, Murray DK, Elliott WL, et al.: Tyrosine kinase inhibitors.14.Structure-activity relationships for methyl-amino-substituted derivatives of4-[(3-bromophenyl)amino]-6(methylamino)-pyrido[3,4-d]pyr-imidine (PD158780), a potent andspeci c inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factor.J Med Chem,1998,41:742-751.
[96] Thompson AM, Murray DK, Elliott WL, et al.: J Med Chem,1997,40:3915-3925.
[97] Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA. J MedChem1997;40:1519.
[98] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802438;1998.
[99] Cockerill GS, Carter MC, Guntrip SB, et al. Glaxo Group WO-09802437;1998.
[100] Cockerill GS, Guntrip SB, McKeown SK, et al., inventors. Glaxo Group WO-09713771;1997.
[101] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-19629652-A1;1998.
[102] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae DE-1960831-A1;1997.
[103] Blankley CJ, Boschelli DH, Doherty AM, et al. Warner Lambert WO-09634867;1996.
[104] Connolly CJC, Hamby JM, Schroeder MC, et al.: Discovery and structure-activity studiesof a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. Bioorg Med Chem Lett,1997,7:2415-2418.
[105] Hamby JM, Connolly CJ, Schroeder MC, et al.: Structure-activity relationships for a novelseries of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem,1997,40:2296-2303.
[106] Mohammadi M, Froum S, Hamby JM, et al.: Crystal structure of an angiogenesis inhibitorbound to the FGF receptor tyrosine kinase domain. EMBO J,1998,17:5896-5904.
[107] Panek RL, Lu GH, Klutchko SR, et al.: a new nanomolar potent and broadly active proteinkinase inhibitor. J Pharmacol Exp Ther,1997,283:1433-1444.
[108] Boschelli DH, Wu Z, Klutchko SR, et al.: synthesis and tyrosine kinase inhibitory activityof a series of2-amino-8H-pyrido[2,3-d]pyrimidines: identigication of potent, selectiveplatelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem,1998,41:4365-4377.
[109] Rewcastle GF, Bridges AJ, Fry DW, et al.: Tyrosine Kinase Inhibitors.12. Synthesis andStructure-Activity Relationships for6-Substituted4-(Phenylamino) pyrimido[5,4-d] pyrimidinesDesigned as Inhibitors of the Epidermal Growth Factor Receptor. J Med Chem,1997,40:1820-1826.
[110] Himmelsbach F, Dahmann G, von Ruden T, et al. Karl Thomae WO-09732880;1997.
[111] Himmelsbach F, Dahmann G, von Ruden T, et al. WO-09732882;1997.
[112] Traxler P, Bold G, Buchdunger E, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[113] Missbach M, Jeschke M, Field JB, et al.: A novel inhibitor of the tyrosine kinase Srcsuppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitroand in rodent models in vivo. Bone,1999,24:437-449.
[114] Missbach M, Green J, Susa M, et al. Book of abstracts. Dallas:215th ACS Nat Meet;1998.
[115] Altmann E, inventor. Novartis AG WO-09734895;1997.
[116] Altmann E, Missbach M, Widler L. Novartis AG WO-09732879;1997.
[117] Altmann E, Missbach M, Widler L, et al. Novartis AG WO-09749706;1997.
[118] Altmann E, Widler L, Missbach M. Novartis AG WO-09728161;1997.
[119] Missbach M. Ciba–Geigy WO-09610028;1996.
[120] Henry JR, Rupert KC, Dodd JH, et al.:6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (RWJ68354): A Potent and Selective p38KinaseInhibitor J Med Chem,1998,41:4196-4198.
[121] Hanke JH, Gardner JP, Dow RL, et al.: Discovery of a novel, potent, and Srcfamily-selective tyrosine kinase Inhibitor: study of Lck-and FynT-dependent T cell activation. JBiol Chem,1996,271:695-701.
[122] Zhu X, Kim JL, Newcomb JR, et al.: Structural analysis of the lymphocyte-specific kinaseLck in complex with non-selective and Src family selective kinase inhibitors. Structure,1999,7:651-661.
[123] Bishop AC, Kung CY, Shah K, et al.: Generation of monospecific nanomolar tyrosinekinase inhibitors via a chemical genetic approach. J Am Chem Soc,1999,121:627-631.
[124] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814451;1998.
[125] Bold G, Frei J, Lang M, et al. Novartis AG WO-09814449;1998.
[126] Tang PC, Sun L, McMahon G, et al. Sugen WO-09850356;1998.
[127] Tang C, Sun L, McMahon G, et al. Sugen WO-09807695;1998.
[128] Sun L, Tran F, App H, et al.: Synthesis and biological evaluations of3-substitutedindolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity towardparticular receptor tyrosine kinases. J Med Chem,1998,41:2588-2603.
[129] Battistini C, Ermoli A, Vioglio S, et al. Pharmacia&Upjohn WO-09745409;1997.
[130] Battistini C, Vioglio S, Buzzetti F, et al. Pharmacia&Upjohn WO-09746551;1997.
[131] McNutt RW, Jung DK, Harris PA, et al., inventors. Glaxo Group WO-09910325;1999.
[132] Lackey K, Chapman D, Crosby RM, et al. Proc Am Assoc Cancer Res1999;40:124.
[133] Davis ST, Dickerson SH, Frye SV, et al. Glaxo Group WO-09915500;1999.
[134] Luzzio MJ, Bramson N, Dickerson S, et al. Proc Am Assoc Cancer Res,1999,40:622.
[135] Parker CW, Entsch B, Letham DS. Inhibitors of cytokinin metabolism I. Inhibition of twoenzymes which metabo-lize cytokinins. Phytochem,1986,25:303-310.
[136] Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol,1996,6:393-397.
[137] Vesely J, Havlicek L, Strnad M, et al. Progress in Cell Cycle Research. Eur J Biochem1994,224:771-786.
[138] MacCallum DE, Melville J, Frame S, et al.: Seliciclib (CYC202, R-Roscovitine) inducescell death in multi-ple myeloma cells by inhibition of RNA polymerase II-dependenttranscription and down-regulation of Mcl-1Cancer Research,2005,65(12):5399–5407.
[139] Noopur Raje, Shaji Kumar, Teru Hideshima, et al.: Seliciclib (CYC202or R-roscovitine), asmall-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation ofMcl-1in multiple myeloma. Blood,2005,106(3):1042–1047.
[140] Rossi AG, Sawatzky DA, Walker A, et al.: Cyclin-dependent kinase inhibitors enhance theresolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine,2006,12(9):1056–1064.
[141] Gray NS, Wodicka L, Thunnissen AMWH, et al.: Exploiting chemical libraries, structure,and genomics in the search for kinase inhibitors. Science,1998,281:533-538.
[142] Imbach P, Capraro HG, Furet P, et al.:2,6,9-trisubstituted purines: optimization towardshighly potent and selective CDK1inhibitors. Bioorg Med Chem Lett,1999,9:91-96.
[143] Adams JL, Boehm JC, Kassis S, et al.: Pyrimidinylimidazole inhibitors of CSBP/p38kinase demonstrating decreased inhibition of hepatic cytochrome P450enzymes. Bioorg MedChem Lett,1998,8:3111-3116.
[144] Jackson JR, Bolognese B, Hillegass L, et al.: Pharmacological Effects of SB220025, aSelective Inhibitor of P38Mitogen-Activated Protein Kinase, in Angiogenesis and ChronicInflammatory Disease Models. J Pharmacol Exp Ther,1998,284:687-692.
[145] Frantz B, Klatt T, Pang M, et al.: Induction of apoptosis by SB202190through inhibitionof p38β mitogen-activated protein kinase. Biochem,1998,37:13846-13853.
[146] Liverton NJ, Butcher JW, Clairbone CF, et al.: Design and Synthesis of Potent, Selective,and Orally Bioavailable Tetrasubstituted Imidazole Inhibitors of p38Mitogen-Activated ProteinKinase. J Med Chem,1999,42:2180-2190.
[147] Heimbrook DC, Huber HE, Stirdivant SM, et al.: Epidermal growth factor induction of thec-jun promoter by a Rac pathway. Proc Am Assoc Cancer Res,1998,39:558-559.
[148] Meyer T, Regenass U, Fabbro D, et al.: A derivative of staurosporine (CGP41251) showsselectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivoanti-tumor activity. Int J Cancer,1989,43:85-856.
[149] Mehta AB, Virchis AE, Jones DT, et al.: The formation of new blood vessels from anexisting vascular network. Blood,1997,90:3634-3641.
[150] P. A. Campochiaro and the C99-PKC412-003Study Group, Invest. Ophthalmol. VisualSci.,2004,45:922–931.
[151] Takahashi I, Kobayashi E, Asano K, et al. UCN-01, a selective inhibitor of protein kinaseC from Streptomyces. J Antibiot,1987,40:1782-1784.
[152] Akinaga S, Sugiyama K, Akiyama T. UCN-01(7-hydroxystaurosporine) and otherindolocarbazole compounds: a new generation of anti-cancer agents for the new century?.Anti-Cancer Drug Des,2000,15:43–52.
[153] K. Grosios, UCN-01Kyowa Hakko Kogyo Co. Curr. Opin. Invest. Drugs (Thomson Sci.),2001,2:287–297.
[154] Senderowicz AM. The Cell Cycle as a Target for Cancer Therapy: Basic and ClinicalFindings with the Small Molecule Inhibitors Flavopiridol and UCN-01. Oncologist,2002,7(suppl.3),12–19.
[155] Butler MS. Natural products to drugs: natural product derived compounds in clinical trials.Nat. Prod. Rep.,2005,22:162–195.
[156] ClinicalTrials.gov (a service of the US National Institutes of Health). Available athttp://clinicaltrials.gov.
[157] Fuse E, Kuwabara T, Sparreboom A, et al.: Review of UCN-01development: a lesson inthe importance of clinical pharmacology. J. Clin. Pharmacol,2005,45:394–403.
[158] Sausville EA. Indifferently Pursued or Unowned Drugs: Who Should Lead WhereCompanies Do Not Tread?. J. Clin. Oncol,2005,23:1796–1798.
[159] Camoratto AM, Jani J P, Angeles TS, et al.: CEP-751inhibits trk receptor tyrosine kinaseactivity in vitro and exhibits anti-tumor activity. Int. J. Cancer,1997,72:673–679.
[160] Ruggeri BA, Miknyoczki SJ, Singh J, et al.: Role of neurotrophin–trk interactions inoncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors inpre-clinical tumor models. Curr. Med. Chem.,1999,6:845–857.
[161] Strock CJ, Park JI, Rosen DM, et al.: Activity of irinotecan and the tyrosine kinaseinhibitor CEP-751in medullary thyroid cancer. J Clin Endocrinol Metab. J. Clin. Endocrinol.Metab.,2006,91:79–84.
[162] Strock CJ, Park JI, Rosen M, et al.: Activated RET Tyrosine Kinase Activity and BlockMedullary Thyroid Carcinoma Cell Growth. Cancer Res.,2003,63:5559–5563.
[163] Brown P, Levis M, McIntyre E, et al.: Constitutively activated FLT3phosphorylates BADpartially through pim-1. Leukemia,2006,20:1368–1376.
[164] Smith BD, Levis M, Beran M, et al.: Single Agent CEP-701, a novel FLT3inhibitor, showsbiologic response and clinical activity in patients with relapsed or refractory acute myeloidleukemia. Blood,2004,103:3669–3676.
[165] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.Invest. New Drugs,2004,22:449–458.
[166] Camoratto AM, Jani JP, Angeles T, Maroney A, et al.: CEP-751inhibits trk receptortyrosine kinase activity in vitro and exhibits anti-tumor activity. Int J Cancer,1997,72:673-679.
[167] Undevia SD, Vogelzang NJ, Mauer AM, et al.: Phase I clinical trial of CEP-2563dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.Invest. New Drugs,2004,22:449–458.
[168] Gingrich DE, Reddy DR, Iqbal MA, et al.: A New Class of Potent Vascular EndothelialGrowth Factor Receptor Tyrosine Kinase Inhibitors: Structure Activity Relationships for aSeries of9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo [3,4-c]carbazole-5-onesand the Identification of CEP-5214and Its Dimethylglycine Ester Prodrug Clinical CandidateCEP-7055. J. Med. Chem.,2003,46:5375–5388.
[169] Jirousek MR, Gillig JR, Gonzalez CM, et al.:(S)-13-[(Dimethylamino)methyl]-10,11,14,15–tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues: Isozyme Selective Inhibitors ofProtein Kinase Cβ. J. Med. Chem.,1996,39:2664–2671.
[170] Tuttle KR, Bakris GL, Toto RD, et al.: The Effect of Ruboxistaurin on Nephropathy inType2Diabetes. Diabetes Care,2005,28:2686–2690.
[171] Vinik AI, Bril V, Kempler P, et al.: Treatment of symptomatic diabetic peripheralneuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a1-year,randomized, placebo-controlled, double-blind clinical trial. Clin. Ther.,2005,27:1164–1180.
[172] Aiello LP, Clermont A, Arora V, et al.: Inhibition of PKC β by Oral Administration ofRuboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal HemodynamicAbnormalities in Patients. Invest. Ophthalmol. Visual Sci.,2006,47:86–92.
[173] Faul MM, Gillig JR, Jirousek MR, et al.: Acyclic N-(azacycloalkyl)bisindolylmaleimides:Isozyme Selective Inhibitors of PKC. Bioorganic&Medicinal Chemistry Letters,2003,13:1857–1859.
[174] Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain ofc-Abl in complex with the small molecule inhibitors PD173955and imatinib (STI-571). CancerRes.2002,62:4236–4243.
[175] Hancock, C.N. et al. Identification of novel extracellular signal-regulated kinase dockingdomain inhibitors. J. Med. Chem.2005,48:4586–4595.
[176] Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design:a molecular modeling perspective. Med Res Rev.,1996,16:3–50.
[177] Hann MM, Oprea TI. Pursuing the leadlikeness concept in pharma-ceutical research. CurrOpin Chem Biol.2004,8:255–263.
[178] Fink T, Bruggesser H, Reymond JL. Virtual exploration of the small-molecule chemicaluniverse below160daltons. Angew Chem Int Ed Engl.2005,44:1504–1508.
[179] Kolb HC, Sharpless KB. The growing impact of click chemistry on drug discovery. DrugDiscovery Today,2003,8,1128–1137.
[180] Whiting M, Tripp JC, Lin YC, et al.: Rapid Discovery and Structure Activity Profiling ofNovel Inhibitors of Human Immunodeficiency Virus Type1Protease Enabled by theCopper(I)-Catalyzed Synthesis of1,2,3-Triazoles and their further functionalization. J.Med.Chem.,2006,49,7697–7710.
[181] Relles. Organic chemistry in thionyl chloride. I. Dichloromaleimide chemistry. II. Thionylchloride-pyridine method for the conversion of maleimides to dichloromaleimides. Howard M. J.Org. Chem.1972,37:3630-3637.
[182] Margaret M. Faul, Kevin A. Sullivan, Leonard L. Winneroski, A geneal approach to thesynthesis of Bisindolymaleimides: Synthesis of Staurosporine Aglycone. Synthesis,1995,12:1511-1516.
[183] J. Bain, H. McLauchlan, M. Elliott and P. Cohen, Biochem. J.,2003,371:199-204.
[184] R. Li and J. A. Staford, Kinase inhibitor drugs, Wiley, Hoboken, NJ,2009.
[185] Noble ME, Endicott JA, Johnson LN. Protein Kinase Inhibitors: Insights into Drug Designfrom Structure. Science,2004,303,1800.
[186] Gill M, Steglich W, in Progress in the Chemistry of Organic Natural Products, ed. W. Herz,H. Grisebach, G. W. Kirby and C. Tamm, Springer-Verlag, New York,1987, vol.51, pp.1–317.
[187] W. Steglich, Pure Appl. Chem.,1989,61,281–288.
[188] Bergman J, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman, Elsevier,Amsterdam,1988, vol.1(Stereoselective synthesis, Part A), pp.3–30.
[189] Bergman J., Janosik T. and N.Wahlstrom, in Advances in Heterocyclic Chemistry, ed. A.Katritzky, Academic Press, New York,2001, vol.80, pp.1–71.
[190] Gribble GW, Berthel SJ, in Studies in Natural Product Chemistry, ed. Atta-ur-Rahman,Elsevier, Amsterdam,1993, vol.12(Stereoselective synthesis, Part H), pp.365–409.
[191] M. Prudhomme, Curr. Pharm. Des.,1997,3,265–290.
[192] M. Prudhomme, Curr. Med. Chem.,2000,7,1189–1212.
[193] M. Prudhomme, Eur. J. Med. Chem.,2003,38,123–140.
[194] Pindur U, Kim YS, Mehrabani F, Curr. Med. Chem.,1999,6,29–69.
[195] Knolker HJ, Reddy KR, Chem. Rev.,2002,102,4303–4427.
[196] Long BH, Rose WC, Vyas DM, et al.: Curr. Med. Chem.: Anti-Cancer Agents,2002,2,255–266.
[197] Kawasaki T, Higuchi K, Nat. Prod. Rep.,2005,22,761–793.
[198] anchez CS′, endez CM′, Salas JA, J. Ind. Microbiol. Biotechnol.,2006,33,560–568.
[199] Omura S, Iwai Y, Hirano A,et al.:, J. Antibiot.,1977,30,275–282.
[200] Funato N, Takayanagi H, Konda Y, et al.: Tetrahedron Lett.,1994,35,1251–1254.
[201] Link JT, Raghavan S, Gallant M, et al.: J. Am. Chem. Soc.,1996,118,2825–2842.
[202] Butler MS, Nat. Prod. Rep.,2005,22,162.
[203] Meksuriyen D, Cordell GA, J. Nat. Prod.,1988,51,893–899.
[204] Yang SW, Cordell GA, J. Nat. Prod.,1996,59,828–833.
[205] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,788–790.
[206] Yang SW, Cordell GA, J. Nat. Prod.,1997,60,236–241.
[207] Yang SW, Lin LJ, Cordell GA, et al. J. Nat. Prod.,1999,62,1551–1553.
[208] Pearce CJ, Doyle TW, Forenza S, et al. J. Nat. Prod.,1988,51,937–940.
[209] Onaka H, Taniguchi S, Igarashi Y, et al. J. Antibiot.,2002,55,1063–1071.
[210] Anchez CS, Zhu L, Bra na AF, et al. Proc. Natl. Acad. Sci. U. S. A.,2005,102,461–466.
[211] Salas AP, Zhu L, Sáanchez C, et al. Mol. Microbiol.,2005,58,17–27.
[212](a) Liu J and Gin DY, J. Am. Chem. Soc.,2002,124,9789;(b) Honda E and Gin DY, J.Am. Chem. Soc.,2002,124,7343;(c) Tiwari P and Misra AK, J. Org. Chem.,2006,71,2911.
[213](a) Jayakanthan K and Vankar YD, Org. Lett.,2005,7,5441;(b) Saeeng R and Isobe M,Org. Lett.,2005,7,1585;(c) Lehmann U, Awasthi S and Minehan T, Org. Lett.,2003,5,2405;(d) V. Di Bussolo, M. Caselli, M. Pineschi, et al. Org. Lett.,2003,5,2173.
[214](a) Yin J, Spindler J andLinker T, Chem. Commun.,2007,2712;(b) Larrosa I, Romea P,Urp F, et al. Org. Lett.,2002,4,4651;(c) Parrish JD andLittle RD, Org. Lett.,2002,4,1439;(d)Rainier JD andCox JM, Org. Lett.,2000,2,2707;(e) Thorn SN and Gallagher T, Synlett,1996,856.
[215](a) Boulineau FP andWei A, Org. Lett.,2004,6,119;(b) Seeberger PH, Eckhardt M,Gutteridge CE, et al, J. Am. Chem. Soc.,1997,119,10064.
[216](a) Dahl RS and Finney NS, J. Am. Chem. Soc.,2004,126,8356;(b). Colinas PA andBravo RD, Org. Lett.,2003,5,4509;(c) Li BQ, Franck RW, Capozzi G, et al. Org. Lett.,1999,1,111.
[217](a) Cousins GS and Hoberg JO, Chem. Soc. Rev.,2000,29,165;(b) Haveli SD, SridharPR, Suguna P, et al. Org. Lett.,2007,9,1331.
[218](a) DiBussolo V, Romano MR, Pineschi M, et al. Org. Lett.,2005,7,1299;(b) Kim JY,Bussolo VD, Gin DY. Org. Lett.,2001,3,303.
[219](a) Roush WR andBennett CE, J. Am. Chem. Soc.,1999,121,3541;(b) DiBussolo V, KimY J, Gin DY, J. Am. Chem. Soc.,1998,120,13515.
[220] Lemieux RU and Ratcliffe RM, Can. J. Chem.,1979,57,1244.
[221] Roth W, Pigman W. Methods Carbohydr. Chem.1963,2,405–408.
[223] Eitelman SJ. Jordaan A. J. Chem. Soc., Chem. Commun.1977,552–553.
[224] Ireland RE, Wilcox CS, Thaisrivongs S. J. Org. Chem.1978,43,786–787.
[225] Spencer RP, Cavallaro CL, Schwartz J. J. Org. Chem.1999,64,3987–3995.
[226]Cavallaro CL, Schwart J. J. Org. Chem.1995,60,7055–7057.
[227] Hansen T, Daasbjerg K, Skrydstrup T. Tetrahedron Lett.2000,41,8645–8649.
[228] Kovács G, Micskei K, Somsák L. Carbohydr. Res.2001,336,225–228.
[229] Pollon, J. H. P.; Llewellyn, G.; Williams, J. M. Synthesis1989,758–759.
[230] Fürstner, A.; Weidmann, H. J. Carbohydr. Chem.1988,7,773–783.
[231] Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth. Commun.1992,22,2459–2477.
[232] Forbes, C. L.; Franck, R. W. J. Org. Chem.1999,64,1424–1425.
[233] Boutureira, O.; Rodríguez, M. A.; Matheu, M. I.; Díaz, Y.; Castillón, S. Org. Lett.2006,8,673–675.
[234] Micskei, K.; Juhász, Z.; Ratkovic, Z. R.; Somsák, L. Tetrahedron Lett.2006,47,6117–6120.
[235] Gómez, A. M.; Casillas, M.; Barrio, A.; Gawel, A.; López, J. C. Eur. J. Org. Chem.2008,3933–3942.
[236] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Green Chem.,2009,11,1124–1127.
[237] Jinzhong Zhao, Shanqiao Wei, Xiaofeng Ma, Huawu Shao. Carbohydrate Research.2010,345,168–171.
[238] Subramaniam Sabesan and Susana Neira J. Org. Chem.,1991,56(18),5468-5472.
[239] Guisheng Zhang, Jie Shen, Hao Cheng, Lizhi Zhu, Lanyan Fang, Sanzhong Luo, Mark T.Muller, Gun Eui Lee, Lijun Wei, Yuguo Du, Duxin Sun, and Peng George Wang. J. Med. Chem.2005,48,2600-2611.
[240] César Sánchez, Aaroa P. Salas, Alfredo F. Bra a, et al. Chem. Commun.,2009,4118-4120.
[241] Yang M, Zhou J, Schneller SW. Tetrahedron2006,62,1295.
[242] Michel BY, Strazewski P. Tetrahedron2007,63,9836.
[243] Kumara Swamy KC, Bhuvan Kumar NN, Balaraman E, et al. Chem. Rev.2009,109,2551–2651.
[244] Wang M, Xu L, Gao MZ, et al.: Enzastaruin, the first design and radiosynthesis of a newpotential PET agent for imaging of protein kinase C. Bioorganic&Medicinal Chemistry letters.2011,21:1649-1653.
[245] Bradford VW, Radhakrishnan U, Joshua C, et al. WO2006020879