小分子靶向c-Fms抑制剂的研究进展
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摘要
巨噬细胞集落刺激因子受体(c-Fms)是原癌基因fms编码的产物,为Ⅲ型酪氨酸激酶。c-Fms及其配体CSF-1在肿瘤相关巨噬细胞的增殖、生长、分化过程中起着重要作用。c-Fms在多种恶性肿瘤和炎性疾病中异常表达,CSF-1/c-Fms轴可能成为治疗恶性肿瘤的有效途径。许多以c-Fms为靶标的小分子抑制剂正在研究与临床开发中。简介c-Fms的结构特征和作用机制,对小分子靶向c-Fms抑制剂的研究进展进行综述,以期为相关研究提供参考。
Macrophage colony stimulating factor receptor(c-Fms), the product encoded by proto-oncogene fms, is a type III receptor tyrosine kinase. c-Fms and its ligand CSF-1 play important roles in the proliferation, growth and differentiation of tumor-associated macrophages. c-Fms is abnormally expressed in a variety of malignant and inflammatory diseases. The CSF-1/c-Fms axis might be an effective approach to the treatment of malignant tumors. Many small molecular inhibitors targeting c-Fms are under research and clinical development. This article describes the mechanisms of c-Fms and its roles in tumor immunotherapy, and reviews the latest research progress in small-molecule inhibitors of c-Fms, so as to provide reference for follow-up studies.
Macrophage colony stimulating factor receptor(c-Fms), the product encoded by proto-oncogene fms, is a type III receptor tyrosine kinase. c-Fms and its ligand CSF-1 play important roles in the proliferation, growth and differentiation of tumor-associated macrophages. c-Fms is abnormally expressed in a variety of malignant and inflammatory diseases. The CSF-1/c-Fms axis might be an effective approach to the treatment of malignant tumors. Many small molecular inhibitors targeting c-Fms are under research and clinical development. This article describes the mechanisms of c-Fms and its roles in tumor immunotherapy, and reviews the latest research progress in small-molecule inhibitors of c-Fms, so as to provide reference for follow-up studies.
引文
[1]Chanmee T, Ontong P, Konno K, et al. Tumor-associated macrophages asmajorplayersinthetumormicroenvironment[J].Cancers, 2014,6(3):1670-1690.
[2]ZhangQW,LiuL,GongC Y,etal.Prognosticsignificanceof tumor-associated macrophages in solid tumor:a meta-analysis of the literature[J]. PLoS One, 2012, 7(12):e50946.
[3]Lin H, Lee E, Hestir K, et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome[J]. Science, 2008,320(5877):807-811.
[4]Chitu V,StanleyER.Colony-stimulatingfactor-1inimmunityand inflammation[J]. Curr Opin Immunol, 2006, 18(1):39-48.
[5]Achkova D, Maher J. Role of the colony-stimulating factor(CSF)/CSF-1 receptor axis in cancer[J]. Biochem Soc Trans, 2016, 44(2):333-341.
[6]Lamprecht B, Walter K, Kreher S, et al. Derepression of an endogenous longterminalrepeatactivatestheCSF1Rproto-oncogeneinhuman lymphoma[J]. Nat Med, 2010, 16(5):571-579.
[7]Sherr C J, Rettenmier C W, Sacca R, et al. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF1[J]. Cell, 1985, 41(3):665-676.
[8]Kowalska M, Tajer J, Chechlinska M, et al. Discriminant analysis involving serum cytokine levels and prediction of the response to therapy of patients with hodgkin lymphoma[J]. Tumour Biol, 2012, 33(5):1733-1738.
[9]Rohrschneider L R, Rothwell V M, Nicola N A. Transformation of murinefibroblastsbyaretrovirusencodingthemurinec-fmsprotooncogene[J]. Oncogene, 1989, 4(8):1015-1022.
[10]Kascinski B. Expression of CSF-1 and its receptor CSF-1R in nonhematopoietic neoplasms[J]. Cancer Treat Res, 2002, 107:285-292.
[11]Wang L, Zheng G G, Ma C H, et al. A special linker between macrophage and hematopoietic malignant cells:membrane form of macrophage colonystimulating factor[J]. Cancer Res, 2008, 68(14):5639-5647.
[12]IlligCR,ChenJ, WallMJ,etal.DiscoveryofnovelFMSkinase inhibitors as anti-inflammatory agents[J]. Bioorg Med Chem Lett, 2008,18(5):1642-1648.
[13]Illig C R, Manthey C L, Wall M J, et al. Optimization of a potent class of arylamide colony-stimulating factor-1 receptor inhibitors leading to anti-inflammatory clinical candidate 4-cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide(JNJ-28312141)[J]. J Med Chem, 2011, 54(22):7860-7883.
[14]MantheyCL,JohnsonDL,IlligCR,etal.JNJ-28312141,anovel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia[J]. Mol Cancer Ther, 2009, 8(11):3151-3161.
[15]Wilson K J, Illig C R, Chen J, et al. Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors[J]. Bioorg Med Chem Lett, 2010, 20(13):3925-3929.
[16]Patch R J, Brandt B M, Asgari D, et al. Potent 2′-aminoanilide inhibitors of c-Fms as potential anti-inflammatory agents[J]. Bioorg Med Chem Lett, 2007, 17(22):6070-6074.
[17]Schubert C, Schalk-hihi C, Struble G T, et al. Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor(c-Fms)in complex with two inhibitors[J]. J Biol Chem, 2007, 282(6):4094-4101.
[18]ImD,JungK, YangS,etal.Discoveryof4-arylamido-3-methyl isoxazolederivativesasnovelFMSkinaseinhibitors[J].EurJMed Chem, 2015, 102:600-610.
[19]Ramachandran S A, Jadhavar P S, Miglani S K, et al. Design, synthesis andoptimizationofbis-amidederivativesasCSF1Rinhibitors[J].Bioorg Med Chem Lett, 2017, 27(10):2153-2160.
[20]Scott D A, Balliet C L, Cook D J, et al. Identification of 3-amido-4-anilinoquinolines as potent and selective inhibitors of CSF-1R kinase[J].Bioorg Med Chem Lett, 2009, 19(3):697-700.
[21]Wall M J, Chen J, Meegalla S, et al. Synthesis and evaluation of novel3,4,6-substituted 2-quinolones as FMS kinase inhibitors[J]. Bioorg Med Chem Lett, 2008, 18(6):2097-2102.
[22]Ohno H, Uemura Y, Murooka H, et al. The orally-active and selective c-Fms tyrosine kinase inhibitor ki20227 inhibits disease progression in a collagen-induced arthritis mouse model[J]. Cent Eur J Immunol, 2008,38(1):283-291.
[23]Ohno H, Kubo K, Murooka H, et al. A c-fms tyrosine kinase inhibitor,ki20227, suppresses osteoclast differentiation and osteolytic bone destructioninabonemetastasismodel[J].MolCancerTher, 2006,5(11):2634-2643.
[24]Kubo K, Ohno H, Isoe T, et al. Quinoline derivatives and quinazoline derivativesinhibitingautophosphorylationofmacrophagecolony stimulating factor receptor:US7598258[P]. 2009-10-06.
[25]ConwayJG,McdonaldB,ParhamJ,etal.Inhibitionofcolonystimulating-factor-1 signaling in vivo with the orally bioavailable c-FMS kinase inhibitor GW2580[J]. Proc Natl Acad Sci USA, 2005, 102(44):16078-16083.
[26]Paniagua R T, Chang A, Mariano M M, et al. c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis[J]. Arthritis Res Ther, 2010, 12(1):R32.
[27]Leblond A L, Klinkert K, Martin K, et al. Systemic and cardiac depletion of M2 Macrophage through CSF-1R signaling inhibition slters cardiac function post myocardial infarction[J]. PLo S One, 2015, 10(9):e0137515.
[28]Farag AK,Elkamhawy A,Londhe AM,etal. Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders[J]. Eur J Med Chem, 2017, 141:657-675.
[29]Zhang C, Ibrahim P N, Zhang J, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor[J]. Proc Natl Acad Sci USA, 2013, 110(14):5689-5694.
[30]Denardo D G, Brennan D J, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy[J]. Cancer Discov, 2011, 1(1):54-67.
[31]CuccareseMF,DubachJM,PfirschkeC,etal.Heterogeneityof macrophageinfiltrationandtherapeuticresponseinlungcarcinoma revealed by 3D organ imaging[J]. Nat Commun, 2017, 8:14293.
[32]Tap W D, Wainberg Z A, Anthony S P, et al. Structure-guided blockade ofCSF1Rkinaseintenosynovialgiant-celltumor[J].NEnglJMed,2015, 373(5):428-437.
[33]ConiglioSJ,EugeninE,DobrenisK,etal.Microglialstimulation ofglioblastomainvasioninvolvesepidermalgrowthfactorreceptor(EGFR)and colony stimulating factor 1 receptor(CSF-1R)signaling[J].Mol Med, 2012, 18(1):519-527.
[34]Chitu V, Nacu V, Charles J F, et al. PSTPIP2 deficiency in mice causes osteopeniaandincreaseddifferentiationofmultipotentmyeloid precursors into osteoclasts[J]. Blood, 2012, 120(15):3126-3135.
[35]Sluijter M, Sluis T C V D, Velden P A V D, et al. Inhibition of CSF-1R supports T-cell mediated melanoma therapy[J]. PLoS One, 2014, 9(8):e104230.
[36]Kim T S, Cavnar M J, Cohen N A, et al. Increased Kit inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor[J]. Clin Cancer Res, 2014, 20(9):2350-2362.
[37]ButowskiN,ColmanH,DeGrootJF,etal.Orallyadministered colonystimulatingfactor1receptorinhibitorPLX3397inrecurrent glioblastoma:an ivy foundation early phase clinical trials consortium phase II study[J]. Neuro Oncol, 2016, 18(4):557-564.
[38]EL-Gamal M I, Abdel-Maksoud M S, El-Din M M G, et al. Cell-based biological evaluation of a new bisamide fms kinase inhibitor possessing pyrrolo[3,2-c]pyridine scaffold[J]. Arch Pharm, 2014, 347(9):635-641.
[39]Pyonteck S M, Akkari L, Schuhmacher A J, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression[J]. Nat Med, 2013, 19(10):1264-1272.
[40]Strachan D C, Brian R, Yoko O, et al. CSF1R inhibition delays cervical andmammarytumorgrowthinmurinemodelsbyattenuatingthe turnover of tumor-associated macrophages and enhancing infiltration by CD8+T cells[J]. Oncoimmunology, 2013, 2(12):e26968.
[41]Bendell J C, Tolcher A W, Jones S F, et al. Abstract A252:a phase 1studyof ARRY-382,anoralinhibitorofcolony-stimulatingfactor-1receptor(CSF1R), in patients with advanced or metastatic cancers[J].Mol Cancer Ther, 2013, 12:A252-A252.
[42]Smith B D, Leary C B, Lu W P, et al. Abstract 4889:the highly specific CSF1R inhibitor DCC-3014 exhibits immunomodulatory and antiinvasive activities in cancer models[J]. Cancer Res, 2016, 76:4889-4889.
[43]Smith B D, Kaufman M D, Leary C B, et al. Abstract A53:The specific FMS kinase inhibitor, DCC-3014, durably inhibits FMS kinase in vivo and blocks cancer bone invasiveness[J]. Cancer Res, 2015, 75:A53-A53.
[44]Dewar A L, Cambareri A C, Zannettino A C, et al. Macrophage colonystimulating factor receptor c-Fms is a novel target of imatinib[J]. Blood,2005, 105(8):3127-3132.
[45]杨胜乾,王莉莉.巨噬细胞集落刺激因子受体激酶及其抑制剂的研究进展[J].国际药学研究杂志, 2010, 37(5):340-345.
[2]ZhangQW,LiuL,GongC Y,etal.Prognosticsignificanceof tumor-associated macrophages in solid tumor:a meta-analysis of the literature[J]. PLoS One, 2012, 7(12):e50946.
[3]Lin H, Lee E, Hestir K, et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome[J]. Science, 2008,320(5877):807-811.
[4]Chitu V,StanleyER.Colony-stimulatingfactor-1inimmunityand inflammation[J]. Curr Opin Immunol, 2006, 18(1):39-48.
[5]Achkova D, Maher J. Role of the colony-stimulating factor(CSF)/CSF-1 receptor axis in cancer[J]. Biochem Soc Trans, 2016, 44(2):333-341.
[6]Lamprecht B, Walter K, Kreher S, et al. Derepression of an endogenous longterminalrepeatactivatestheCSF1Rproto-oncogeneinhuman lymphoma[J]. Nat Med, 2010, 16(5):571-579.
[7]Sherr C J, Rettenmier C W, Sacca R, et al. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF1[J]. Cell, 1985, 41(3):665-676.
[8]Kowalska M, Tajer J, Chechlinska M, et al. Discriminant analysis involving serum cytokine levels and prediction of the response to therapy of patients with hodgkin lymphoma[J]. Tumour Biol, 2012, 33(5):1733-1738.
[9]Rohrschneider L R, Rothwell V M, Nicola N A. Transformation of murinefibroblastsbyaretrovirusencodingthemurinec-fmsprotooncogene[J]. Oncogene, 1989, 4(8):1015-1022.
[10]Kascinski B. Expression of CSF-1 and its receptor CSF-1R in nonhematopoietic neoplasms[J]. Cancer Treat Res, 2002, 107:285-292.
[11]Wang L, Zheng G G, Ma C H, et al. A special linker between macrophage and hematopoietic malignant cells:membrane form of macrophage colonystimulating factor[J]. Cancer Res, 2008, 68(14):5639-5647.
[12]IlligCR,ChenJ, WallMJ,etal.DiscoveryofnovelFMSkinase inhibitors as anti-inflammatory agents[J]. Bioorg Med Chem Lett, 2008,18(5):1642-1648.
[13]Illig C R, Manthey C L, Wall M J, et al. Optimization of a potent class of arylamide colony-stimulating factor-1 receptor inhibitors leading to anti-inflammatory clinical candidate 4-cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide(JNJ-28312141)[J]. J Med Chem, 2011, 54(22):7860-7883.
[14]MantheyCL,JohnsonDL,IlligCR,etal.JNJ-28312141,anovel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia[J]. Mol Cancer Ther, 2009, 8(11):3151-3161.
[15]Wilson K J, Illig C R, Chen J, et al. Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors[J]. Bioorg Med Chem Lett, 2010, 20(13):3925-3929.
[16]Patch R J, Brandt B M, Asgari D, et al. Potent 2′-aminoanilide inhibitors of c-Fms as potential anti-inflammatory agents[J]. Bioorg Med Chem Lett, 2007, 17(22):6070-6074.
[17]Schubert C, Schalk-hihi C, Struble G T, et al. Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor(c-Fms)in complex with two inhibitors[J]. J Biol Chem, 2007, 282(6):4094-4101.
[18]ImD,JungK, YangS,etal.Discoveryof4-arylamido-3-methyl isoxazolederivativesasnovelFMSkinaseinhibitors[J].EurJMed Chem, 2015, 102:600-610.
[19]Ramachandran S A, Jadhavar P S, Miglani S K, et al. Design, synthesis andoptimizationofbis-amidederivativesasCSF1Rinhibitors[J].Bioorg Med Chem Lett, 2017, 27(10):2153-2160.
[20]Scott D A, Balliet C L, Cook D J, et al. Identification of 3-amido-4-anilinoquinolines as potent and selective inhibitors of CSF-1R kinase[J].Bioorg Med Chem Lett, 2009, 19(3):697-700.
[21]Wall M J, Chen J, Meegalla S, et al. Synthesis and evaluation of novel3,4,6-substituted 2-quinolones as FMS kinase inhibitors[J]. Bioorg Med Chem Lett, 2008, 18(6):2097-2102.
[22]Ohno H, Uemura Y, Murooka H, et al. The orally-active and selective c-Fms tyrosine kinase inhibitor ki20227 inhibits disease progression in a collagen-induced arthritis mouse model[J]. Cent Eur J Immunol, 2008,38(1):283-291.
[23]Ohno H, Kubo K, Murooka H, et al. A c-fms tyrosine kinase inhibitor,ki20227, suppresses osteoclast differentiation and osteolytic bone destructioninabonemetastasismodel[J].MolCancerTher, 2006,5(11):2634-2643.
[24]Kubo K, Ohno H, Isoe T, et al. Quinoline derivatives and quinazoline derivativesinhibitingautophosphorylationofmacrophagecolony stimulating factor receptor:US7598258[P]. 2009-10-06.
[25]ConwayJG,McdonaldB,ParhamJ,etal.Inhibitionofcolonystimulating-factor-1 signaling in vivo with the orally bioavailable c-FMS kinase inhibitor GW2580[J]. Proc Natl Acad Sci USA, 2005, 102(44):16078-16083.
[26]Paniagua R T, Chang A, Mariano M M, et al. c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis[J]. Arthritis Res Ther, 2010, 12(1):R32.
[27]Leblond A L, Klinkert K, Martin K, et al. Systemic and cardiac depletion of M2 Macrophage through CSF-1R signaling inhibition slters cardiac function post myocardial infarction[J]. PLo S One, 2015, 10(9):e0137515.
[28]Farag AK,Elkamhawy A,Londhe AM,etal. Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders[J]. Eur J Med Chem, 2017, 141:657-675.
[29]Zhang C, Ibrahim P N, Zhang J, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor[J]. Proc Natl Acad Sci USA, 2013, 110(14):5689-5694.
[30]Denardo D G, Brennan D J, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy[J]. Cancer Discov, 2011, 1(1):54-67.
[31]CuccareseMF,DubachJM,PfirschkeC,etal.Heterogeneityof macrophageinfiltrationandtherapeuticresponseinlungcarcinoma revealed by 3D organ imaging[J]. Nat Commun, 2017, 8:14293.
[32]Tap W D, Wainberg Z A, Anthony S P, et al. Structure-guided blockade ofCSF1Rkinaseintenosynovialgiant-celltumor[J].NEnglJMed,2015, 373(5):428-437.
[33]ConiglioSJ,EugeninE,DobrenisK,etal.Microglialstimulation ofglioblastomainvasioninvolvesepidermalgrowthfactorreceptor(EGFR)and colony stimulating factor 1 receptor(CSF-1R)signaling[J].Mol Med, 2012, 18(1):519-527.
[34]Chitu V, Nacu V, Charles J F, et al. PSTPIP2 deficiency in mice causes osteopeniaandincreaseddifferentiationofmultipotentmyeloid precursors into osteoclasts[J]. Blood, 2012, 120(15):3126-3135.
[35]Sluijter M, Sluis T C V D, Velden P A V D, et al. Inhibition of CSF-1R supports T-cell mediated melanoma therapy[J]. PLoS One, 2014, 9(8):e104230.
[36]Kim T S, Cavnar M J, Cohen N A, et al. Increased Kit inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor[J]. Clin Cancer Res, 2014, 20(9):2350-2362.
[37]ButowskiN,ColmanH,DeGrootJF,etal.Orallyadministered colonystimulatingfactor1receptorinhibitorPLX3397inrecurrent glioblastoma:an ivy foundation early phase clinical trials consortium phase II study[J]. Neuro Oncol, 2016, 18(4):557-564.
[38]EL-Gamal M I, Abdel-Maksoud M S, El-Din M M G, et al. Cell-based biological evaluation of a new bisamide fms kinase inhibitor possessing pyrrolo[3,2-c]pyridine scaffold[J]. Arch Pharm, 2014, 347(9):635-641.
[39]Pyonteck S M, Akkari L, Schuhmacher A J, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression[J]. Nat Med, 2013, 19(10):1264-1272.
[40]Strachan D C, Brian R, Yoko O, et al. CSF1R inhibition delays cervical andmammarytumorgrowthinmurinemodelsbyattenuatingthe turnover of tumor-associated macrophages and enhancing infiltration by CD8+T cells[J]. Oncoimmunology, 2013, 2(12):e26968.
[41]Bendell J C, Tolcher A W, Jones S F, et al. Abstract A252:a phase 1studyof ARRY-382,anoralinhibitorofcolony-stimulatingfactor-1receptor(CSF1R), in patients with advanced or metastatic cancers[J].Mol Cancer Ther, 2013, 12:A252-A252.
[42]Smith B D, Leary C B, Lu W P, et al. Abstract 4889:the highly specific CSF1R inhibitor DCC-3014 exhibits immunomodulatory and antiinvasive activities in cancer models[J]. Cancer Res, 2016, 76:4889-4889.
[43]Smith B D, Kaufman M D, Leary C B, et al. Abstract A53:The specific FMS kinase inhibitor, DCC-3014, durably inhibits FMS kinase in vivo and blocks cancer bone invasiveness[J]. Cancer Res, 2015, 75:A53-A53.
[44]Dewar A L, Cambareri A C, Zannettino A C, et al. Macrophage colonystimulating factor receptor c-Fms is a novel target of imatinib[J]. Blood,2005, 105(8):3127-3132.
[45]杨胜乾,王莉莉.巨噬细胞集落刺激因子受体激酶及其抑制剂的研究进展[J].国际药学研究杂志, 2010, 37(5):340-345.