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摘要: 蛋白激酶的异常功能与肿瘤密切相关，通过研发相应的蛋白激酶抑制剂调控对应的信号转导通路是现今抗肿瘤药物开发的重点与热点。自从第一种蛋白激酶抑制剂在2001年被美国食品药品监督管理局（FDA）批准上市以来，已有50余种激酶抑制剂获得批准用于治疗乳腺癌和肺癌等恶性肿瘤，在肿瘤患者的治疗中起到重要的作用。小分子蛋白激酶抑制剂同样存在许多亟待解决的问题，为此，研究者不断地开发新的激酶靶向药物来克服发现的问题，许多新的小分子激酶抑制剂已处于临床试验阶段。本综述就抗肿瘤小分子蛋白激酶抑制剂的分类、作用底物以及作用机理进行分析和总结，并系统阐述抗肿瘤小分子激酶抑制剂的研发现状、研究进展和发展趋势。
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关键词:
- 蛋白激酶 /
- 小分子蛋白激酶抑制剂 /
- 肿瘤 /
- 分子靶向治疗
Abstract: Abnormal function of protein kinases has been closely related to tumors and thus, the development of corresponding protein kinase inhibitors to regulate the relevant signal transduction pathways is the current focus of anti-tumor drug development research. Since the first protein kinase inhibitor was licensed by the FDA in 2001, more than 50 protein kinase inhibitors have been approved for the treatment of malignant tumors such as breast and lung cancers, playing important roles in cancertreatment. However, small molecule kinase inhibitors also have several issues that need to be addressed. Hence, researchers continue to develop new kinase-targeting drugs to resolve these issues. Nevertheless, many new small molecule kinase inhibitors are being tested in clinical trials. This review summarizes the classification, substrates, and anti-tumor mechanisms of small molecule protein kinase inhibitors. Moreover, the advances in research and trends in the development of anti-tumor small molecule kinase inhibitors have been described systematically. -
表 1 FDA批准的小分子抑制剂及其主要适应证
表 2 处于各期临床试验的小分子蛋白激酶抑制剂
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[1] Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion[J]. Nature, 1984, 308(5961):693-698. doi: 10.1038/308693a0 [2] Goel HL, Mercurio AM. VEGF targets the tumour cell[J]. Nat Rev Cancer, 2013, 13(12):871-882. doi: 10.1038/nrc3627 [3] Turner N, Grose R. Fibroblast growth factor signalling:from development to cancer[J]. Nat Rev Cancer, 2010, 10(2):116-129. doi: 10.1038/nrc2780 [4] Zhang Z, Zhang D, Liu Y, et al. Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases:Preclinical and clinical developments of small molecule inhibitors[J]. Arch Pharm (Weinheim), 2018, 351(7):e1700369. doi: 10.1002/ardp.201700369 [5] Sykes SM, Lane SW, Bullinger L, et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias[J]. Cell, 2011, 146(5):697-708. doi: 10.1016/j.cell.2011.07.032 [6] Li S, Song Y, Quach C, et al. Transcriptional regulation of autophagylysosomal function in BRAF- driven melanoma progression and chemoresistance[J]. Nat Commun, 2019, 10(1):1693. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461621/ [7] Bedard PL, Hyman DM, Davids MS, et al. Small molecules, big impact:20 years of targeted therapy in oncology[J]. Lancet, 2020, 395(10229):1078-1088. doi: 10.1016/S0140-6736(20)30164-1 [8] Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors[J]. Nat Rev Cancer, 2009, 9(1):28-39. doi: 10.1038/nrc2559 [9] Knighton DR, Zheng JH, Ten Eyck LF, et al. Crystal structure of the catalytic subunit of cyclic adenosinemonophosphate-dependent protein kinase[J]. Science, 1991, 253:407-414. doi: 10.1126/science.1862342 [10] Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations[J]. Nat Chem Biol, 2006, 2(7):358-364. doi: 10.1038/nchembio799 [11] Lamba V, Ghosh I. New directions in targeting protein kinases:focusing upon true allosteric and bivalent inhibitors[J]. Curr Pharm Des, 2012, 18(20):2936-2945. doi: 10.2174/138161212800672813 [12] Cohen MS, Zhang C, Shokat KM, et al. Structural bioinformatics-based design of selective, irreversible kinase inhibitors[J]. Science, 2005, 308(5726):1318-1321. doi: 10.1126/science1108367 [13] Brattas MK, Reikvam H, Tvedt THA, et al. Dasatinib as an investigational drug for the treatment of Philadelphia chromosome- positive acute lymphoblastic leukemia in adults[J]. Expert Opin Investig Drugs, 2019, 28(5):411-420. doi: 10.1080/13543784.2019.1597052 [14] Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias[J]. N Engl J Med, 2006, 354(24):2531-2541. doi: 10.1056/NEJMoa055229 [15] Garmendia I, Pajares MJ, Hermida-Prado F, et al. YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib[J]. Am J Respir Crit Care Med, 2019, 200(7):888-899. doi: 10.1164/rccm.201807-1292OC [16] Heigener DF, Reck M. Crizotinib[J]. Recent Results Cancer Res, 2018, 211:57-65. http://d.old.wanfangdata.com.cn/Periodical/jcyxylc201303027 [17] Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia[J]. N Engl J Med, 2017, 376(10):917-927. doi: 10.1056/NEJMoa1609324 [18] Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib:randomised trial[J]. Lancet, 2004, 364(9440):1127-1134. doi: 10.1016/S0140-6736(04)17098-0 [19] Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL[J]. N Engl J Med, 2006, 354(24):2542-2551. doi: 10.1056/NEJMoa055104 [20] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma[J]. N Engl J Med, 2007, 356(2):125-134. doi: 10.1056/NEJMoa060655 [21] Lim HY, Merle P, Weiss KH, et al. Phase Ⅱ studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma[J]. Clin Cancer Res, 2018, 24(19):4650-4661. doi: 10.1158/1078-0432.CCR-17-3588 [22] Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040(PD184352), a targeted signal transduction inhibitor of MEK (MAPKK)[J]. Semin Oncol, 2003, 30(5 Suppl 16):105-116. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=d0f034b080e5511f52d592c32521c3ce [23] Fasano M, Della Corte CM, Califano R, et al. Type Ⅲor allosteric kinase inhibitors for the treatment of non-small cell lung cancer[J]. Expert Opin Investig Drugs, 2014, 23(6):809-821. doi: 10.1517/13543784.2014.902934 [24] Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib[J]. N Engl J Med, 2015, 372(1):30-39. doi: 10.1056/NEJMoa1412690 [25] Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure[J]. Engl J Med, 2019, 381(24):2315-2326. doi: 10.1056/NEJMoa1902328 [26] Schoepfer J, Jahnke W, Berellini G, et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1[J]. J Med Chem, 2018, 61(18):8120-8135. doi: 10.1021/acs.jmedchem.8b01040 [27] Abdallah SM, Hirsh V. Irreversible tyrosine kinase inhibition of epidermal growth factor receptor with afatinib in EGFR activating mutation-positive advanced non-small cell lung cancer[J]. Curr Oncol, 2018, 25(Suppl 1):S9-S17. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=408511b876df809dc4979ecc65d01dbd [28] Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumabbased adjuvant therapy in HER2-positive breast cancer (ExteNET):5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2017, 18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9 [29] Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for firstline treatment of CLL[J]. N Engl J Med, 2019, 380(22):2095-2103. doi: 10.1056/NEJMoa1900574 [30] Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatmentnaive chronic lymphocytic leukaemia (ELEVATE TN):a randomised, controlled, phase 3 trial[J]. Lancet, 2020, 395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2 [31] Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer[J]. N Engl J Med, 2020, 382(7):597-609. doi: 10.1056/NEJMoa1914609 [32] Ahn MJ, Han JY, Lee KH, et al. Lazertinib in patients with EGFR mutationpositive advanced non-smal cell lung cancer:results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study[J]. Lancet Oncol, 2019, 20(12):1681-1690. doi: 10.1016/S1470-2045(19)30504-2 [33] Kim DW, Lee DH, Han JY, et al. Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation:A single arm, open label, phase 1/2 trial[J]. Lung Cancer, 2019, 135:66-72. doi: 10.1016/j.lungcan.2019.07.007 [34] Fountzilas C, Gupta M, Lee S, et al. A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma[J].Br J Cancer, 2020, 122(7):963-970. doi: 10.1038/s41416-020-0737-6 [35] Jones RL, Ratain MJ, O'Dwyer PJ, et al. Phase Ⅱ randomised discontinuation trial of brivanib in patients with advanced solid tumours[J]. Eur J Cancer, 2019, 120:132-139. doi: 10.1016/j.ejca.2019.07.024 [36] Chen CI, Paul H, Le LW, et al. A phase 2 study of ofatumumab (Arzerra® in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL)[J]. Leuk Lymphoma, 2019, 60(1):92-100. doi: 10.1080/10428194.2018.1468892 [37] Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS):a multicentre, randomised, double- blind, placebocontrolled, phase 2 trial[J]. Lancet Oncol, 2017, 18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3 [38] Sequist LV, Han JY, Ahn MJ, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small cell lung cancer after progression on EGFR tyrosine kinase inhibitors:interim results from a multicentre, open-label, phase 1b study[J]. Lancet Oncol, 2020, 21(3):373-386. doi: 10.1016/S1470-2045(19)30785-5 [39] Kochanny SE, Worden FP, Adkins DR, et al. A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma[J]. Cancer, 2020, 126(10):2146-2152. doi: 10.1002/cncr.32762 [40] Falchook GS, Kurzrock R, Amin HM, et al. First-in-man phase i trial of the selective MET inhibitor tepotinib in patients with advanced solid tumors[J]. Clin Cancer Res, 2020, 26(6):1237-1246. doi: 10.1158/1078-0432.CCR-19-2860 [41] Sohn SH, Kim B, Sul HJ, et al. Foretinib inhibits cancer stemness and gastric cancer cell proliferation by decreasing CD44 and c-MET signaling[J]. Onco Targets Ther, 2020, 13:1027-1035. doi: 10.2147/OTT.S226951 [42] Rubinstein MM, Hyman DM, Caird I, et al. Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway[J]. Cancer, 2020, 126(6):1274-1282. doi: 10.1002/cncr.32677 [43] Langdon SP, Kay C, Um IH, et al. Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models[J]. Sci Rep, 2019, 9(1):18742. doi: 10.1038/s41598-019-55096-9 [44] Lapointe S, Mason W, MacNeil M, et al. A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme:a CCTG study[J]. Invest New Drugs, 2019, doi: 10.1007/s10637-019-00875-4. [45] Patwardhan PP, Ivy KS, Musi E, et al. Significant blockade of multiple receptor tyrosine kinases by MGCD516(Sitravatinib), a novel small molecule inhibitor, shows potent anti- tumor activity in preclinical models of sarcoma[J]. Oncotarget, 2016, 7(4):4093-4109. doi: 10.18632/oncotarget.6547 [46] Wu CP, Hsiao SH, Huang YH, et al. Sitravatinib sensitizes ABCB1- and ABCG2- overexpressing multidrug- resistant cancer cells to chemotherapeutic drugs[J]. Cancers (Basel), 2020, 12(1):195. doi: 10.3390/cancers12010195 [47] Wang M, Liu Y, Cheng Y, et al. Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment[J]. Biochim Biophys Acta Rev Cancer, 2019, 1871(2):199-224. doi: 10.1016/j.bbcan.2018.12.002 -
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