酪氨酸激酶抑制剂类小分子抗肿瘤药物的研究进展
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摘要
酪氨酸激酶在肿瘤发生发展过程中扮演着重要的角色,以其为导向的分子靶向药物研发已成为现代抗肿瘤药物发展的主流趋势之一,近年来已取得重大进展。本文总结并综述了近年来30余种已上市的酪氨酸激酶抑制剂类小分子抗肿瘤靶向药物,同时概述了相关类似物结构改造的研究进展和趋势。
Many studies have demonstrated that protein tyrosine kinases play an important role in the development of tumors. Thus the molecular targeted drugs based on tyrosine kinases have become one of the important trends for R&D of innovative antitumor drugs,and remarkable achievements have been made in recent years. In this paper,according to a wide range of literature,more than 30 marketed small-molecule anticancer drugs targeting tyrosine kinases were reviewed,and the development progress of novel analogues was summarized and discussed.
Many studies have demonstrated that protein tyrosine kinases play an important role in the development of tumors. Thus the molecular targeted drugs based on tyrosine kinases have become one of the important trends for R&D of innovative antitumor drugs,and remarkable achievements have been made in recent years. In this paper,according to a wide range of literature,more than 30 marketed small-molecule anticancer drugs targeting tyrosine kinases were reviewed,and the development progress of novel analogues was summarized and discussed.
引文
[1] LEMMON MA,SCHLESSINGER J. Cell signaling by receptor tyrosine kinases[J]. Cell,2010,141(7):1117-1134.
[2] MOSLEHI JJ,DEININGER M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia[J]. J Clin Oncol,2015,33(35):4210-4218.
[3] ROBINSON DR,WU YM,LIN SF. The protein tyrosine kinase family of the human genome[J]. Oncogene,2000,19(49):5548-5557.
[4] CHOURA M,REBAI A. Receptor tyrosine kinases:from biology to pathology[J]. J Recept Sig Transd,2011,31(6):387-394.
[5] HOJJAT-FARSANGI M. Targeting non-receptor tyrosine kinases using small molecule inhibitors:an overview of recent advances[J]. J Drug Target,2016,24(3):192-211.
[6] ADAMS JA. Kinetic and catalytic mechanisms of protein kinases[J]. Chem Rev,2001,101(8):2271-2290.
[7] TRAXLER P,BOLD G,BUCHDUNGER E,et al. Tyrosine kinase inhibitors:from rational design to clinical trials[J]. Med Res Rev,2001,21(6):499-512.
[8] DE ML,KYRITSIS V. Clinical efficacy of generic imatinib[J].J Oncol Pharm Pract,2015,21(1):76-79.
[9] EMOLE J,TALABI T,PINILLA-IBARZ J. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia:role of nilotinib[J]. Biol Tar Ther,2016,10:23-31.
[10] YAO RS,GUAN QX,LU XQ,et al. Design,synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Ablkinase[J]. Lett Drug Des Discov,2015,12(1):20-28.
[11]徐芹,陈南,张美慧,等.伊马替尼类似物的设计合成及体外抗增殖活性研究[J].中国药物化学杂志,2016,26(4):273-279.
[12] TIWARI RK,BROWN A,SADEGHIANI N,et al. Design,synthesis,and evaluation of dasatinib-amino acid and dasatinib-fatty acid conjugates as protein tyrosine kinase inhibitors[J]. Chem Med Chem,2017,12(1):86-99.
[13]郭宗儒.以经典药物化学方法研发的达拉非尼[J].药学学报,2014,49(5):747-750.
[14] LONG GV,FLAHERTY KT,STROYAKOVSKIY D,et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma:long-term survival and safety analysis of a phase 3 study[J]. Ann Oncol,2017,28(7):1631-1639.
[15]郭宗儒.首创性的“跟踪”药物色瑞替尼[J].药学学报,2017,52(3):500-504.
[16] HUANG WS,LIU S,ZOU D,et al. Discovery ofbrigatinib(AP26113),a phosphine oxide-containing,potent,orally active inhibitor of anaplastic lymphoma kinase[J]. J Med Chem,2016,59(10):4948-4964.
[17] SJIN RTT,LEE K,WALTER AO,et al. In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing[J]. Mol Cancer Ther,2014,13(6):1468-1479.
[18] EISEN T,STERNBERG CN,ROBERT C,et al. Targeted therapies for renal cell carcinoma:review of adverse event management strategies[J]. Jnci J Natl Cancer Inst,2012,104(2):93-113.
[19] XIE C,ZHOU J,GUO Z,et al. Metabolism and bioactivation of famitinib,a novel inhibitor of receptor tyrosine kinase,in cancer patients[J]. Brit J Pharmacol,2013,168(7):1687-1706.
[20] RICCIUTI B,BAGLIVO S,PAGLIALUNGA L,et al. Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer:rationale,evidence and place in therapy[J]. Ther Adv Med Oncol,2017,9(6):387-403.
[21] WARD RA,ANDERTON MJ,ASHTON S,et al. Structure-and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor(EGFR)[J]. J Med Chem,2013,56(17):7025-7048.
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[23] SHAGUFT A,AHMAD I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents[J]. Med Chem Comm,2017,8(5):871-885.
[24]袁熙.新型替尼类药物的设计与合成[D].北京:北京化工大学,2016.
[25] ZHAO F,LIN Z,WANG F,et al. Four-membered heterocyclescontaining 4-anilino-quinazoline derivatives as epidermal growth factor receptor(EGFR)kinase inhibitors[J]. Bioorg Med Chem Lett,2013,23(19):5385-5388.
[26] WU XQ,LI MD,QU Y,et al. Design and synthesis of novel gefitinib analogues with improved anti-tumor activity[J]. Bioorg Med Chem,2010,18(11):3812-3822.
[27] TAN F,SHI Y,WANG Y,et al. Icotinib,a selective EGF receptor tyrosine kinase inhibitor,for the treatment of non-smallcell lung cancer[J]. Future Oncol,2015,11(3):385-397.
[28] LYU AF,FANG L,GOU SH. Design and synthesis of lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates[J]. Eur J Med Chem,2014,87:631-642.
[29]李高全,张翠芳,谢爱云,等.聚乙二醇化拉帕替尼及其注射剂和制备方法,中国:CN104987504A[P]. 2015.
[30]赖宜生,庞俊霞,罗明昊,等.α-氰基-α,β-不饱和酰胺类化合物及其医药用途,中国:CN104774184A[P]. 2015.
[31] SERAFIMOVA IM,PUFALL M,KRISHNAN S,et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles[J]. Nat ChemBiol,2012,8(5):471-476.
[32] TU YB,OUYANG YQ,XU S,et al. Design,synthesis,and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors[J]. Bioorg Med Chem,2016,24(7):1495-1503.
[33] WU C,WANG M,TANG Q,et al. Design,synthesis,activity and docking study of sorafenib analogs bearing sulfonylurea unit[J]. Molecules,2015,20(10):19361-19371.
[34] WILLIAMS TE,SUBRAMANIAN S,VERHAGEN J,et al. Discovery of RAF265:a potent mut-B-Raf inhibitor for the treatment of metastatic melanoma[J]. ACS Med Chem Lett,2015,6(9):961-965.
[35] WANG M,XU S,WU C,et al. Design,synthesis and activity of novel sorafenib analogues bearing chalcone unit[J]. Bioorg Med Chem Lett,2016,26(22):5450-5454.
[36] DZOLIC ZR,PERKOVIC I,PAVELIC SK,et al. Design,synthesis,and cytostatic activity of novel pyrazine sorafenib analogs[J]. Med Chem Res,2016,25(12):2729-2741.
[37] JIAO Y,XIN BT,ZHANG Y,et al. Design,synthesis and evaluation of novel 2-(1H-imidazol-2-yl)pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents[J]. Eur J Med Chem,2015,90:170-183.
[38] BRUIX J,QIN SK,MERLE P,et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE):a randomised,double-blind,placebo-controlled,phase 3 trial[J]. Lancet,2017,389(10064):56-66.
[39]胡月,娄金凤,刘景瑞,等.甲苯磺酸多纳非尼治疗原发性肝癌长期缓解2例报告[J].临床肝胆病杂志,2017,33(4):730-731.
[40] CORTES JE,KHOURY HJ,KANTARJIAN HM,et al. Longterm bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib[J]. Am J Hematol,2016,91(12):1206-1214.
[41] CAO X,YOU QD,LI Z-Y,et al. Design and synthesis of 7-alkoxy-4-heteroarylamino-3-quinolinecarbonitriles as dual inhibitors of c-Src kinase and nitric oxide synthase[J]. Bioorgan Med Chem,2008,16(11):5890-5898.
[42] BUTI S,BERSANELLI M. Is cabozantinib really better than sunitinib as first-line treatment of metastatic renal cell carcinoma?[J]. J Clin Oncol,2017,35(16):1858-1859.
[43] BROSE MS,WORDEN FP,NEWBOLD KL,et al. Effect of ageon the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial[J]. J Clin Oncol,2017,35(23):2692-2699.
[44]李伟,雷春花,王立强,等.多靶点受体酪氨酸激酶抑制剂喹啉衍生物的合成及活性初步研究[J].中国新药杂志,2016,25(13):1522-1530.
[45] POON CC,KELLY JJ. Development of crizotinib,a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer[J]. Int J Cancer,2017,140(9):1945-1954.
[46] JOHNSON TW,RICHARDSON PF,BAILEY S,et al. Discovery of(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile(PF-06463922),a macrocyclic inhibitor of anaplastic lymphoma kinase(ALK)and c-ros oncogene 1(ROS1)with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations[J]. J Med Chem,2014,57(11):4720-4744.
[47] BASIT S,ASHRAF Z,LEE K,et al. First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer:clinical and designing strategy update of lorlatinib[J]. Eur J Med Chem,2017,134:348-356.
[48] ROVIELLO G,RAVELLI A,POLOM K,et al. Apatinib:a novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer[J]. Cancer Lett,2016,372(2):187-191.
[49] FRAMPTON JE. Pazopanib:a review in advanced renal cell carcinoma[J]. Target Oncol,2017,12(4):543-554.
[50] NAKAHARA Y,FUKUI T,KATONO K,et al. Pneumothorax during pazopanib treatment in patients with soft-tissue sarcoma:two case reports and a review of the literature[J]. Case Rep Oncol,2017,10(1):333-338.
[51] SONG J,YOO J,KWON A,et al. Structure-activity relationship of indole-tethered pyrimidine derivatives that concurrently inhibit epidermal growth factor receptor and other angiokinases[J]. Plos One,2015,10(9):e0138823.
[52] PEMOVSKA T,JOHNSON E,KONTRO M,et al. Axitinib effectively inhibits BCR-ABL1(T315I)with a distinct binding conformation[J]. Nature,2015,519(7541):102.
[53] WU D,GUO M,PHILIPS MA,et al. Crystal Structure of the FGFR4/LY2874455 complex reveals insights into the pan-FGFR selectivity of LY2874455[J]. Plos One, 2016, 11(9):e0162491.
[54] LELAIS G,EPPLE R,MARSILJE TH,et al. Discovery of(R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl] azepan-3-yl)-1H-benzo[d] imidazol-2-yl)-2-methylisonicotinamide(EGF816),a novel,potent,and WT sparing covalent inhibitor of oncogenic(L858R,ex19del)and resistant(T790M)EGFR mutants for the treatment of EGFR mutant non-small-cell lung cancers[J]. J Med Chem,2016,59(14):6671-6689.
[55] LIU Y,PENG X,GUAN X,et al. Discovery of novel ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors[J]. Eur J Med Chem,2017,126:122-132.
[56] CUI Z,CHEN S,WANG Y,et al. Design,synthesis and evaluation of a zaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment[J]. Eur J Med Chem,2017,136:372-381.
[57] CUI Z,LI X,LI L,et al. Design,synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment[J]. Bioorgan Med Chem,2016,24(2):261-269.
[2] MOSLEHI JJ,DEININGER M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia[J]. J Clin Oncol,2015,33(35):4210-4218.
[3] ROBINSON DR,WU YM,LIN SF. The protein tyrosine kinase family of the human genome[J]. Oncogene,2000,19(49):5548-5557.
[4] CHOURA M,REBAI A. Receptor tyrosine kinases:from biology to pathology[J]. J Recept Sig Transd,2011,31(6):387-394.
[5] HOJJAT-FARSANGI M. Targeting non-receptor tyrosine kinases using small molecule inhibitors:an overview of recent advances[J]. J Drug Target,2016,24(3):192-211.
[6] ADAMS JA. Kinetic and catalytic mechanisms of protein kinases[J]. Chem Rev,2001,101(8):2271-2290.
[7] TRAXLER P,BOLD G,BUCHDUNGER E,et al. Tyrosine kinase inhibitors:from rational design to clinical trials[J]. Med Res Rev,2001,21(6):499-512.
[8] DE ML,KYRITSIS V. Clinical efficacy of generic imatinib[J].J Oncol Pharm Pract,2015,21(1):76-79.
[9] EMOLE J,TALABI T,PINILLA-IBARZ J. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia:role of nilotinib[J]. Biol Tar Ther,2016,10:23-31.
[10] YAO RS,GUAN QX,LU XQ,et al. Design,synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Ablkinase[J]. Lett Drug Des Discov,2015,12(1):20-28.
[11]徐芹,陈南,张美慧,等.伊马替尼类似物的设计合成及体外抗增殖活性研究[J].中国药物化学杂志,2016,26(4):273-279.
[12] TIWARI RK,BROWN A,SADEGHIANI N,et al. Design,synthesis,and evaluation of dasatinib-amino acid and dasatinib-fatty acid conjugates as protein tyrosine kinase inhibitors[J]. Chem Med Chem,2017,12(1):86-99.
[13]郭宗儒.以经典药物化学方法研发的达拉非尼[J].药学学报,2014,49(5):747-750.
[14] LONG GV,FLAHERTY KT,STROYAKOVSKIY D,et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma:long-term survival and safety analysis of a phase 3 study[J]. Ann Oncol,2017,28(7):1631-1639.
[15]郭宗儒.首创性的“跟踪”药物色瑞替尼[J].药学学报,2017,52(3):500-504.
[16] HUANG WS,LIU S,ZOU D,et al. Discovery ofbrigatinib(AP26113),a phosphine oxide-containing,potent,orally active inhibitor of anaplastic lymphoma kinase[J]. J Med Chem,2016,59(10):4948-4964.
[17] SJIN RTT,LEE K,WALTER AO,et al. In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing[J]. Mol Cancer Ther,2014,13(6):1468-1479.
[18] EISEN T,STERNBERG CN,ROBERT C,et al. Targeted therapies for renal cell carcinoma:review of adverse event management strategies[J]. Jnci J Natl Cancer Inst,2012,104(2):93-113.
[19] XIE C,ZHOU J,GUO Z,et al. Metabolism and bioactivation of famitinib,a novel inhibitor of receptor tyrosine kinase,in cancer patients[J]. Brit J Pharmacol,2013,168(7):1687-1706.
[20] RICCIUTI B,BAGLIVO S,PAGLIALUNGA L,et al. Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer:rationale,evidence and place in therapy[J]. Ther Adv Med Oncol,2017,9(6):387-403.
[21] WARD RA,ANDERTON MJ,ASHTON S,et al. Structure-and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor(EGFR)[J]. J Med Chem,2013,56(17):7025-7048.
[22]刘燊. EGFR酪氨酸激酶抑制剂的设计、合成及生物活性筛选和类药性化合物库的构建[D].杭州:浙江大学,2015.
[23] SHAGUFT A,AHMAD I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents[J]. Med Chem Comm,2017,8(5):871-885.
[24]袁熙.新型替尼类药物的设计与合成[D].北京:北京化工大学,2016.
[25] ZHAO F,LIN Z,WANG F,et al. Four-membered heterocyclescontaining 4-anilino-quinazoline derivatives as epidermal growth factor receptor(EGFR)kinase inhibitors[J]. Bioorg Med Chem Lett,2013,23(19):5385-5388.
[26] WU XQ,LI MD,QU Y,et al. Design and synthesis of novel gefitinib analogues with improved anti-tumor activity[J]. Bioorg Med Chem,2010,18(11):3812-3822.
[27] TAN F,SHI Y,WANG Y,et al. Icotinib,a selective EGF receptor tyrosine kinase inhibitor,for the treatment of non-smallcell lung cancer[J]. Future Oncol,2015,11(3):385-397.
[28] LYU AF,FANG L,GOU SH. Design and synthesis of lapatinib derivatives containing a branched side chain as HER1/HER2 targeting antitumor drug candidates[J]. Eur J Med Chem,2014,87:631-642.
[29]李高全,张翠芳,谢爱云,等.聚乙二醇化拉帕替尼及其注射剂和制备方法,中国:CN104987504A[P]. 2015.
[30]赖宜生,庞俊霞,罗明昊,等.α-氰基-α,β-不饱和酰胺类化合物及其医药用途,中国:CN104774184A[P]. 2015.
[31] SERAFIMOVA IM,PUFALL M,KRISHNAN S,et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles[J]. Nat ChemBiol,2012,8(5):471-476.
[32] TU YB,OUYANG YQ,XU S,et al. Design,synthesis,and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors[J]. Bioorg Med Chem,2016,24(7):1495-1503.
[33] WU C,WANG M,TANG Q,et al. Design,synthesis,activity and docking study of sorafenib analogs bearing sulfonylurea unit[J]. Molecules,2015,20(10):19361-19371.
[34] WILLIAMS TE,SUBRAMANIAN S,VERHAGEN J,et al. Discovery of RAF265:a potent mut-B-Raf inhibitor for the treatment of metastatic melanoma[J]. ACS Med Chem Lett,2015,6(9):961-965.
[35] WANG M,XU S,WU C,et al. Design,synthesis and activity of novel sorafenib analogues bearing chalcone unit[J]. Bioorg Med Chem Lett,2016,26(22):5450-5454.
[36] DZOLIC ZR,PERKOVIC I,PAVELIC SK,et al. Design,synthesis,and cytostatic activity of novel pyrazine sorafenib analogs[J]. Med Chem Res,2016,25(12):2729-2741.
[37] JIAO Y,XIN BT,ZHANG Y,et al. Design,synthesis and evaluation of novel 2-(1H-imidazol-2-yl)pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents[J]. Eur J Med Chem,2015,90:170-183.
[38] BRUIX J,QIN SK,MERLE P,et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE):a randomised,double-blind,placebo-controlled,phase 3 trial[J]. Lancet,2017,389(10064):56-66.
[39]胡月,娄金凤,刘景瑞,等.甲苯磺酸多纳非尼治疗原发性肝癌长期缓解2例报告[J].临床肝胆病杂志,2017,33(4):730-731.
[40] CORTES JE,KHOURY HJ,KANTARJIAN HM,et al. Longterm bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib[J]. Am J Hematol,2016,91(12):1206-1214.
[41] CAO X,YOU QD,LI Z-Y,et al. Design and synthesis of 7-alkoxy-4-heteroarylamino-3-quinolinecarbonitriles as dual inhibitors of c-Src kinase and nitric oxide synthase[J]. Bioorgan Med Chem,2008,16(11):5890-5898.
[42] BUTI S,BERSANELLI M. Is cabozantinib really better than sunitinib as first-line treatment of metastatic renal cell carcinoma?[J]. J Clin Oncol,2017,35(16):1858-1859.
[43] BROSE MS,WORDEN FP,NEWBOLD KL,et al. Effect of ageon the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial[J]. J Clin Oncol,2017,35(23):2692-2699.
[44]李伟,雷春花,王立强,等.多靶点受体酪氨酸激酶抑制剂喹啉衍生物的合成及活性初步研究[J].中国新药杂志,2016,25(13):1522-1530.
[45] POON CC,KELLY JJ. Development of crizotinib,a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer[J]. Int J Cancer,2017,140(9):1945-1954.
[46] JOHNSON TW,RICHARDSON PF,BAILEY S,et al. Discovery of(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile(PF-06463922),a macrocyclic inhibitor of anaplastic lymphoma kinase(ALK)and c-ros oncogene 1(ROS1)with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations[J]. J Med Chem,2014,57(11):4720-4744.
[47] BASIT S,ASHRAF Z,LEE K,et al. First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer:clinical and designing strategy update of lorlatinib[J]. Eur J Med Chem,2017,134:348-356.
[48] ROVIELLO G,RAVELLI A,POLOM K,et al. Apatinib:a novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer[J]. Cancer Lett,2016,372(2):187-191.
[49] FRAMPTON JE. Pazopanib:a review in advanced renal cell carcinoma[J]. Target Oncol,2017,12(4):543-554.
[50] NAKAHARA Y,FUKUI T,KATONO K,et al. Pneumothorax during pazopanib treatment in patients with soft-tissue sarcoma:two case reports and a review of the literature[J]. Case Rep Oncol,2017,10(1):333-338.
[51] SONG J,YOO J,KWON A,et al. Structure-activity relationship of indole-tethered pyrimidine derivatives that concurrently inhibit epidermal growth factor receptor and other angiokinases[J]. Plos One,2015,10(9):e0138823.
[52] PEMOVSKA T,JOHNSON E,KONTRO M,et al. Axitinib effectively inhibits BCR-ABL1(T315I)with a distinct binding conformation[J]. Nature,2015,519(7541):102.
[53] WU D,GUO M,PHILIPS MA,et al. Crystal Structure of the FGFR4/LY2874455 complex reveals insights into the pan-FGFR selectivity of LY2874455[J]. Plos One, 2016, 11(9):e0162491.
[54] LELAIS G,EPPLE R,MARSILJE TH,et al. Discovery of(R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl] azepan-3-yl)-1H-benzo[d] imidazol-2-yl)-2-methylisonicotinamide(EGF816),a novel,potent,and WT sparing covalent inhibitor of oncogenic(L858R,ex19del)and resistant(T790M)EGFR mutants for the treatment of EGFR mutant non-small-cell lung cancers[J]. J Med Chem,2016,59(14):6671-6689.
[55] LIU Y,PENG X,GUAN X,et al. Discovery of novel ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors[J]. Eur J Med Chem,2017,126:122-132.
[56] CUI Z,CHEN S,WANG Y,et al. Design,synthesis and evaluation of a zaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment[J]. Eur J Med Chem,2017,136:372-381.
[57] CUI Z,LI X,LI L,et al. Design,synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment[J]. Bioorgan Med Chem,2016,24(2):261-269.