Recent Progress in the Development of Small Molecule c-Met Inhibitors

Peng-Cheng      Lv; Yu-Shun      Yang; Zhong-Chang      Wang
Abstract

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.
Keywords: c-Met, Tyrosine kinase, Small molecule inhibitors, Structure-activity relationship analysis, Anticancer agents, Drug development.
« Previous Next »
Graphical Abstract

[1] 
Trusolino, L.; Bertotti, A.; Comoglio, P.M. MET signalling: Principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol.,  2010, 11(12), 834-848.
[http://dx.doi.org/10.1038/nrm3012] [PMID:  21102609] 
[2] 
Dean, M.; Park, M.; Le Beau, M.M.; Robins, T.S.; Diaz, M.O.; Rowley, J.D.; Blair, D.G.; Vande Woude, G.F. The human met oncogene is related to the tyrosine kinase oncogenes. Nature,  1985, 318(6044), 385-388.
[http://dx.doi.org/10.1038/318385a0] [PMID:  4069211] 
[3] 
Bladt, F.; Riethmacher, D.; Isenmann, S.; Aguzzi, A.; Birchmeier, C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature,  1995, 376(6543), 768-771.
[http://dx.doi.org/10.1038/376768a0] [PMID:  7651534] 
[4] 
Chmielowiec, J.; Borowiak, M.; Morkel, M.; Stradal, T.; Munz, B.; Werner, S.; Wehland, J.; Birchmeier, C.; Birchmeier, W. c-Met is essential for wound healing in the skin. J. Cell Biol.,  2007, 177(1), 151-162.
[http://dx.doi.org/10.1083/jcb.200701086] [PMID:  17403932] 
[5] 
Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science,  2002, 298(5600), 1912-1934.
[http://dx.doi.org/10.1126/science.1075762] [PMID:  12471243] 
[6] 
Corso, S.; Comoglio, P.M.; Giordano, S. Cancer therapy: can the challenge be MET? Trends Mol. Med.,  2005, 11(6), 284-292.
[http://dx.doi.org/10.1016/j.molmed.2005.04.005] [PMID:  15949770] 
[7] 
Szturz, P.; Raymond, E.; Abitbol, C.; Albert, S.; de Gramont, A.; Faivre, S. Understanding c-MET signalling in squamous cell carcinoma of the head & neck. Crit. Rev. Oncol. Hematol.,  2017, 111, 39-51.
[http://dx.doi.org/10.1016/j.critrevonc.2017.01.004] [PMID:  28259294] 
[8] 
Kim, B.; Jung, N.; Lee, S.; Sohng, J.K.; Jung, H.J. Apigenin inhibits cancer stem cell like phenotypes in human Glioblastoma cells via suppression of c-Met Signaling. Phytother. Res.,  2016, 30(11), 1833-1840.
[http://dx.doi.org/10.1002/ptr.5689] [PMID:  27468969] 
[9] 
Lutterbach, B.; Zeng, Q.; Davis, L.J.; Hatch, H.; Hang, G.; Kohl, N.E.; Gibbs, J.B.; Pan, B.S. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res.,  2007, 67(5), 2081-2088.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3495] [PMID:  17332337] 
[10] 
Engelman, J.A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland, C.; Park, J.O.; Lindeman, N.; Gale, C.M.; Zhao, X.; Christensen, J.; Kosaka, T.; Holmes, A.J.; Rogers, A.M.; Cappuzzo, F.; Mok, T.; Lee, C.; Johnson, B.E.; Cantley, L.C.; Jänne, P.A. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science,  2007, 316(5827), 1039-1043.
[http://dx.doi.org/10.1126/science.1141478] [PMID:  17463250] 
[11] 
Bean, J.; Brennan, C.; Shih, J.Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S.; Balak, M.; Chang, W.C.; Yu, C.J.; Gazdar, A.; Pass, H.; Rusch, V.; Gerald, W.; Huang, S.F.; Yang, P.C.; Miller, V.; Ladanyi, M.; Yang, C.H.; Pao, W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA,  2007, 104(52), 20932-20937.
[http://dx.doi.org/10.1073/pnas.0710370104] [PMID:  18093943] 
[12] 
Bradley, C.A.; Salto-Tellez, M.; Laurent-Puig, P.; Bardelli, A.; Rolfo, C.; Tabernero, J.; Khawaja, H.A.; Lawler, M.; Johnston, P.G.; Van Schaeybroeck, S. MErCuRIC consortium. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat. Rev. Clin. Oncol.,  2017, 14(9), 562-576.
[http://dx.doi.org/10.1038/nrclinonc.2017.40] [PMID:  28374784] 
[13] 
Yin, B.; Liu, Z.; Wang, Y.; Wang, X.; Liu, W.; Yu, P.; Duan, X.; Liu, C.; Chen, Y.; Zhang, Y.; Pan, X.; Yao, H.; Liao, Z.; Tao, Z. RON and c-Met facilitate metastasis through the ERK signaling pathway in prostate cancer cells. Oncol. Rep.,  2017, 37(6), 3209-3218.
[http://dx.doi.org/10.3892/or.2017.5585] [PMID:  28440432] 
[14] 
Hass, R.; Jennek, S.; Yang, Y.; Friedrich, K. c-Met expression and activity in urogenital cancers - novel aspects of signal transduction and medical implications. Cell Commun. Signal.,  2017, 15(1), 10.
[http://dx.doi.org/10.1186/s12964-017-0165-2] [PMID:  28212658] 
[15] 
Rucki, A.A.; Xiao, Q.; Muth, S.; Chen, J.; Che, X.; Kleponis, J.; Sharma, R.; Anders, R.A.; Jaffee, E.M.; Zheng, L. Dual inhibition of hedgehog and c-met pathways for pancreatic cancer treatment. Mol. Cancer Ther.,  2017, 16(11), 2399-2409.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0452] [PMID:  28864680] 
[16] 
Zhu, L.; Xiong, X.; Kim, Y.; Okada, N.; Lu, F.; Zhang, H.; Sun, H. Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells. J. Cell Sci.,  2016, 129(22), 4238-4251.
[http://dx.doi.org/10.1242/jcs.191684] [PMID:  27802163] 
[17] 
Gherardi, E.; Birchmeier, W.; Birchmeier, C.; Vande Woude, G. Targeting MET in cancer: Rationale and progress. Nat. Rev. Cancer,  2012, 12(2), 89-103.
[http://dx.doi.org/10.1038/nrc3205] [PMID:  22270953] 
[18] 
Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol.,  2003, 4(12), 915-925.
[http://dx.doi.org/10.1038/nrm1261] [PMID:  14685170] 
[19] 
Boccaccio, C.; Comoglio, P.M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer,  2006, 6(8), 637-645.
[http://dx.doi.org/10.1038/nrc1912] [PMID:  16862193] 
[20] 
Ma, P.C.; Tretiakova, M.S.; MacKinnon, A.C.; Ramnath, N.; Johnson, C.; Dietrich, S.; Seiwert, T.; Christensen, J.G.; Jagadeeswaran, R.; Krausz, T.; Vokes, E.E.; Husain, A.N.; Salgia, R. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer,  2008, 47(12), 1025-1037.
[http://dx.doi.org/10.1002/gcc.20604] [PMID:  18709663] 
[21] 
Cui, J.J. Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress. J. Med. Chem.,  2014, 57(11), 4427-4453.
[http://dx.doi.org/10.1021/jm401427c] [PMID:  24320965] 
[22] 
Al-U’datt, D.G.F.; Al-Husein, B.A.A.; Qasaimeh, G.R. A mini-review of c-Met as a potential therapeutic target in melanoma. Biomed. Pharmacother.,  2017, 88, 194-202.
[http://dx.doi.org/10.1016/j.biopha.2017.01.045] [PMID:  28107696] 
[23] 
Cecchi, F.; Rabe, D.C.; Bottaro, D.P. Targeting the HGF/Met signalling pathway in cancer. Eur. J. Cancer,  2010, 46(7), 1260-1270.
[http://dx.doi.org/10.1016/j.ejca.2010.02.028] [PMID:  20303741] 
[24] 
Peters, S.; Adjei, A.A. MET: a promising anticancer therapeutic target. Nat. Rev. Clin. Oncol.,  2012, 9(6), 314-326.
[http://dx.doi.org/10.1038/nrclinonc.2012.71] [PMID:  22566105] 
[25] 
Fu, Y.T.; Zheng, H.B.; Zhou, L.; Zhang, D.Q.; Liu, X.L.; Sun, H. Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway. Am. J. Transl. Res.,  2017, 9(6), 3138-3147.
[PMID:  28670399] 
[26] 
Liu, W.T.; Jing, Y.Y.; Yu, G.F.; Chen, H.; Han, Z.P.; Yu, D.D.; Fan, Q.M.; Ye, F.; Li, R.; Gao, L.; Zhao, Q.D.; Wu, M.C.; Wei, L.X. Hepatic stellate cell promoted hepatoma cell invasion via the HGF/c-Met signaling pathway regulated by p53. Cell Cycle,  2016, 15(7), 886-894.
[http://dx.doi.org/10.1080/15384101.2016.1152428] [PMID:  27077227] 
[27] 
Zhang, Y.; Du, Z.; Zhang, M. Biomarker development in MET-targeted therapy. Oncotarget,  2016, 7(24), 37370-37389.
[http://dx.doi.org/10.18632/oncotarget.8276] [PMID:  27013592] 
[28] 
Bender, S.; Gronych, J.; Warnatz, H.J.; Pfister, S.M.; Lichter, P.; Jones, D.T. International cancer genome consortium PedBrain tumor project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat. Med.,  2016, 22(11), 1314-1320.
[http://dx.doi.org/10.1038/nm.4204] [PMID:  27748748] 
[29] 
Leung, E.; Xue, A.; Wang, Y.; Rougerie, P.; Sharma, V.P.; Eddy, R.; Cox, D.; Condeelis, J. Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene,  2017, 36(19), 2680-2692.
[http://dx.doi.org/10.1038/onc.2016.421] [PMID:  27893712] 
[30] 
Bahrami, A.; Shahidsales, S.; Khazaei, M.; Ghayour-Mobarhan, M.; Maftouh, M.; Hassanian, S.M.; Avan, A. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. J. Cell. Physiol.,  2017, 232(10), 2657-2673.
[http://dx.doi.org/10.1002/jcp.25794] [PMID:  28075018] 
[31] 
Barrow-McGee, R.; Kishi, N.; Joffre, C.; Ménard, L.; Hervieu, A.; Bakhouche, B.A.; Noval, A.J.; Mai, A.; Guzmán, C.; Robbez-Masson, L.; Iturrioz, X.; Hulit, J.; Brennan, C.H.; Hart, I.R.; Parker, P.J.; Ivaska, J.; Kermorgant, S. Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes. Nat. Commun.,  2016, 7, 11942.
[http://dx.doi.org/10.1038/ncomms11942] [PMID:  27336951] 
[32] 
Caenepeel, S.; Cooke, K.; Wadsworth, S.; Huang, G.; Robert, L.; Moreno, B.H.; Parisi, G.; Cajulis, E.; Kendall, R.; Beltran, P.; Ribas, A.; Coxon, A.; Hughes, P.E. MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor. Oncotarget,  2017, 8(11), 17795-17809.
[http://dx.doi.org/10.18632/oncotarget.14855] [PMID:  28147313] 
[33] 
Cecchi, F.; Rabe, D.C.; Bottaro, D.P. Targeting the HGF/Met signaling pathway in cancer therapy. Expert Opin. Ther. Targets,  2012, 16(6), 553-572.
[http://dx.doi.org/10.1517/14728222.2012.680957] [PMID:  22530990] 
[34] 
Backes, A.; Zech, B.; Felber, B.; Klebl, B.; Müller, G. Small-molecule inhibitors binding to protein kinases. Part I: Exceptions from the traditional pharmacophore approach of type I inhibition. Expert Opin. Drug Discov.,  2008, 3(12), 1409-1425.
[http://dx.doi.org/10.1517/17460440802579975] [PMID:  23506106] 
[35] 
Backes, A.; Zech, B.; Felber, B.; Klebl, B.; Müller, G. Small-molecule inhibitors binding to protein kinase. Part II: The novel pharmacophore approach of type II and type III inhibition. Expert Opin. Drug Discov.,  2008, 3(12), 1427-1449.
[http://dx.doi.org/10.1517/17460440802580106] [PMID:  23506107] 
[36] 
Dussault, I.; Bellon, S.F. From concept to reality: the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer. Anticancer. Agents Med. Chem.,  2009, 9(2), 221-229.
[http://dx.doi.org/10.2174/187152009787313792] [PMID:  19199866] 
[37] 
Bellon, S.F.; Kaplan-Lefko, P.; Yang, Y.; Zhang, Y.; Moriguchi, J.; Rex, K.; Johnson, C.W.; Rose, P.E.; Long, A.M.; O’Connor, A.B.; Gu, Y.; Coxon, A.; Kim, T.S.; Tasker, A.; Burgess, T.L.; Dussault, I. c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J. Biol. Chem.,  2008, 283(5), 2675-2683.
[http://dx.doi.org/10.1074/jbc.M705774200] [PMID:  18055465] 
[38] 
Dussault, I.; Bellon, S.F. c-Met inhibitors with different binding modes: two is better than one. Cell Cycle,  2008, 7(9), 1157-1160.
[http://dx.doi.org/10.4161/cc.7.9.5827] [PMID:  18418040] 
[39] 
Katz, J.D.; Jewell, J.P.; Guerin, D.J.; Lim, J.; Dinsmore, C.J.; Deshmukh, S.V.; Pan, B.S.; Marshall, C.G.; Lu, W.; Altman, M.D.; Dahlberg, W.K.; Davis, L.; Falcone, D.; Gabarda, A.E.; Hang, G.; Hatch, H.; Holmes, R.; Kunii, K.; Lumb, K.J.; Lutterbach, B.; Mathvink, R.; Nazef, N.; Patel, S.B.; Qu, X.; Reilly, J.F.; Rickert, K.W.; Rosenstein, C.; Soisson, S.M.; Spencer, K.B.; Szewczak, A.A.; Walker, D.; Wang, W.; Young, J.; Zeng, Q. Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer. J. Med. Chem.,  2011, 54(12), 4092-4108.
[http://dx.doi.org/10.1021/jm200112k] [PMID:  21608528] 
[40] 
Kataoka, Y.; Mukohara, T.; Tomioka, H.; Funakoshi, Y.; Kiyota, N.; Fujiwara, Y.; Yashiro, M.; Hirakawa, K.; Hirai, M.; Minami, H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest. New Drugs,  2012, 30(4), 1352-1360.
[http://dx.doi.org/10.1007/s10637-011-9699-0] [PMID:  21655918] 
[41] 
Underiner, T.L.; Herbertz, T.; Miknyoczki, S.J. Discovery of small molecule c-Met inhibitors: Evolution and profiles of clinical candidates. Anticancer. Agents Med. Chem.,  2010, 10(1), 7-27.
[http://dx.doi.org/10.2174/1871520611009010007] [PMID:  20015007] 
[42] 
Norman, M.H.; Liu, L.; Lee, M.; Xi, N.; Fellows, I.; D’Angelo, N.D.; Dominguez, C.; Rex, K.; Bellon, S.F.; Kim, T.S.; Dussault, I. Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives. J. Med. Chem.,  2012, 55(5), 1858-1867.
[http://dx.doi.org/10.1021/jm201330u] [PMID:  22320343] 
[43] 
Parikh, P.K.; Ghate, M.D. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur. J. Med. Chem.,  2017, 14(3), 134-145.
[PMID:  29157685] 
[44] 
Qi, B.; Mi, B.; Zhai, X.; Xu, Z.; Zhang, X.; Tian, Z.; Gong, P. Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors. Bioorg. Med. Chem.,  2013, 21(17), 5246-5260.
[http://dx.doi.org/10.1016/j.bmc.2013.06.026] [PMID:  23838381] 
[45] 
Peterson, Q.P.; Hsu, D.C.; Goode, D.R.; Novotny, C.J.; Totten, R.K.; Hergenrother, P.J. Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3. J. Med. Chem.,  2009, 52(18), 5721-5731.
[http://dx.doi.org/10.1021/jm900722z] [PMID:  19708658] 
[46] 
Liu, T.; Sun, C.; Xing, X.; Jing, L.; Tan, R.; Luo, Y.; Huang, W.; Song, H.; Li, Z.; Zhao, Y. Synthesis and evaluation of 2-[2-(phenylthiomethyl)-1H-benzo[d] imidazol-1-yl)acetohydrazide derivatives as antitumor agents. Bioorg. Med. Chem. Lett.,  2012, 22(9), 3122-3125.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.061] [PMID:  22483608] 
[47] 
Straussman, R.; Morikawa, T.; Shee, K.; Barzily-Rokni, M.; Qian, Z.R.; Du, J.; Davis, A.; Mongare, M.M.; Gould, J.; Frederick, D.T.; Cooper, Z.A.; Chapman, P.B.; Solit, D.B.; Ribas, A.; Lo, R.S.; Flaherty, K.T.; Ogino, S.; Wargo, J.A.; Golub, T.R. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature,  2012, 487(7408), 500-504.
[http://dx.doi.org/10.1038/nature11183] [PMID:  22763439] 
[48] 
Jia, J.; Zhu, F.; Ma, X.; Cao, Z.; Cao, Z.W.; Li, Y.; Li, Y.X.; Chen, Y.Z. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov.,  2009, 8(2), 111-128.
[http://dx.doi.org/10.1038/nrd2683] [PMID:  19180105] 
[49] 
Peruzzi, B.; Bottaro, D.P. Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res.,  2006, 12(12), 3657-3660.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0818] [PMID:  16778093] 
[50] 
Liu, X.; Newton, R.C.; Scherle, P.A. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol. Med.,  2010, 16(1), 37-45.
[http://dx.doi.org/10.1016/j.molmed.2009.11.005] [PMID:  20031486] 
[51] 
Bottaro, D.P.; Rubin, J.S.; Faletto, D.L.; Chan, A.M.L.; Kmiecik, T.E.; Vande Woude, G.F.; Aaronson, S.A. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science,  1991, 251(4995), 802-804.
[http://dx.doi.org/10.1126/science.1846706] [PMID:  1846706] 
[52] 
Dean, M.; Park, M.; Le Beau, M.M.; Robins, T.S.; Diaz, M.O.; Rowley, J.D.; Blair, D.G.; Vande Woude, G.F. The human met oncogene is related to the tyrosine kinase oncogenes. Nature,  1985, 318(6044), 385-388.
[http://dx.doi.org/10.1038/318385a0] [PMID:  4069211] 
[53] 
Longati, P.; Comoglio, P.M.; Bardelli, A. Receptor tyrosine kinases as therapeutic targets: The model of the MET oncogene. Curr. Drug Targets,  2001, 2(1), 41-55.
[http://dx.doi.org/10.2174/1389450013348920] [PMID:  11465538] 
[54] 
Comoglio, P.M.; Trusolino, L. Invasive growth: from development to metastasis. J. Clin. Invest.,  2002, 109(7), 857-862.
[http://dx.doi.org/10.1172/JCI0215392] [PMID:  11927611] 
[55] 
Abidoye, O.; Murukurthy, N.; Salgia, R. Review of clinic trials: agents targeting c-Met. Rev. Recent Clin. Trials,  2007, 2(2), 143-147.
[http://dx.doi.org/10.2174/157488707780599357] [PMID:  18473999] 
[56] 
Huh, C.G.; Factor, V.M.; Sánchez, A.; Uchida, K.; Conner, E.A.; Thorgeirsson, S.S. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl. Acad. Sci. USA,  2004, 101(13), 4477-4482.
[http://dx.doi.org/10.1073/pnas.0306068101] [PMID:  15070743] 
[57] 
Brinkmann, V.; Foroutan, H.; Sachs, M.; Weidner, K.M.; Birchmeier, W. Hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells. J. Cell Biol.,  1995, 131(6 Pt 1), 1573-1586.
[http://dx.doi.org/10.1083/jcb.131.6.1573] [PMID:  8522613] 
[58] 
Cui, J.J. Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress. J. Med. Chem.,  2014, 57(11), 4427-4453.
[http://dx.doi.org/10.1021/jm401427c] [PMID:  24320965] 
[59] 
Eder, J.P.; Vande Woude, G.F.; Boerner, S.A.; LoRusso, P.M. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin. Cancer Res.,  2009, 15(7), 2207-2214.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1306] [PMID:  19318488] 
[60] 
Zeng, Z.S.; Weiser, M.R.; Kuntz, E.; Chen, C.T.; Khan, S.A.; Forslund, A.; Nash, G.M.; Gimbel, M.; Yamaguchi, Y.; Culliford, A.T., IV; D’Alessio, M.; Barany, F.; Paty, P.B. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett.,  2008, 265(2), 258-269.
[http://dx.doi.org/10.1016/j.canlet.2008.02.049] [PMID:  18395971] 
[61] 
Benvenuti, S.; Comoglio, P.M. The MET receptor tyrosine kinase in invasion and metastasis. J. Cell. Physiol.,  2007, 213(2), 316-325.
[http://dx.doi.org/10.1002/jcp.21183] [PMID:  17607709] 
[62] 
Shinomiya, N.; Vande Woude, G.F. Suppression of met expression: a possible cancer treatment. Commentary re: S. J. Kim et al., reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin. Cancer Res.,  2003, 9(14), 5085-5090.
[PMID:  14613985] 
[63] 
Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol.,  2003, 4(12), 915-925.
[http://dx.doi.org/10.1038/nrm1261] [PMID:  14685170] 
[64] 
Maulik, G.; Shrikhande, A.; Kijima, T.; Ma, P.C.; Morrison, P.T.; Salgia, R. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev.,  2002, 13(1), 41-59.
[http://dx.doi.org/10.1016/S1359-6101(01)00029-6] [PMID:  11750879] 
[65] 
Sawada, K.; Radjabi, A.R.; Shinomiya, N.; Kistner, E.; Kenny, H.; Becker, A.R.; Turkyilmaz, M.A.; Salgia, R.; Yamada, S.D.; Vande Woude, G.F.; Tretiakova, M.S.; Lengyel, E. c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res.,  2007, 67(4), 1670-1679.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1147] [PMID:  17308108] 
[66] 
Cheng, H.L.; Trink, B.; Tzai, T.S.; Liu, H.S.; Chan, S.H.; Ho, C.L.; Sidransky, D.; Chow, N.H. Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation. J. Clin. Oncol.,  2002, 20(6), 1544-1550.
[http://dx.doi.org/10.1200/JCO.2002.20.6.1544] [PMID:  11896103] 
[67] 
Lengyel, E.; Prechtel, D.; Resau, J.H.; Gauger, K.; Welk, A.; Lindemann, K.; Salanti, G.; Richter, T.; Knudsen, B.; Vande Woude, G.F.; Harbeck, N. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int. J. Cancer,  2005, 113(4), 678-682.
[http://dx.doi.org/10.1002/ijc.20598] [PMID:  15455388] 
[68] 
Lo Muzio, L.; Farina, A.; Rubini, C.; Coccia, E.; Capogreco, M.; Colella, G.; Leonardi, R.; Campisi, G.; Carinci, F. Effect of c-Met expression on survival in head and neck squamous cell carcinoma. Tumour Biol.,  2006, 27(3), 115-121.
[http://dx.doi.org/10.1159/000092716] [PMID:  16612144] 
[69] 
Drebber, U.; Baldus, S.E.; Nolden, B.; Grass, G.; Bollschweiler, E.; Dienes, H.P.; Hölscher, A.H.; Mönig, S.P. The overexpression of c-met as a prognostic indicator for gastric carcinoma compared to p53 and p21 nuclear accumulation. Oncol. Rep.,  2008, 19(6), 1477-1483.
[PMID:  18497953] 
[70] 
Cooper, C.S.; Park, M.; Blair, D.G.; Tainsky, M.A.; Huebner, K.; Croce, C.M.; Vande Woude, G.F. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature,  1984, 311(5981), 29-33.
[http://dx.doi.org/10.1038/311029a0] [PMID:  6590967] 
[71] 
Peruzzi, B.; Bottaro, D.P. Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res.,  2006, 12(12), 3657-3660.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0818] [PMID:  16778093] 
[72] 
Zhu, X.; Giordano, T.; Yu, Q.S.; Holloway, H.W.; Perry, T.A.; Lahiri, D.K.; Brossi, A.; Greig, N.H. Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J. Med. Chem.,  2003, 46(24), 5222-5229.
[http://dx.doi.org/10.1021/jm030152f] [PMID:  14613324] 
[73] 
Kim, K.J.; Wang, L.; Su, Y.C.; Gillespie, G.Y.; Salhotra, A.; Lal, B.; Laterra, J. Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts. Clin. Cancer Res.,  2006, 12(4), 1292-1298.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1793] [PMID:  16489086] 
[74] 
Lu, D.; Shen, A.; Liu, Y.; Peng, X.; Xing, W.; Ai, J.; Geng, M.; Hu, Y. Design and synthesis of novel benzo[d]oxazol-2(3H)-one derivatives bearing 7-substituted-4-enthoxyquinoline moieties as c-Met kinase inhibitors. Eur. J. Med. Chem.,  2016, 115, 191-200.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.027] [PMID:  27017548] 
[75] 
Qiang, H.; Gu, W.; Huang, D.; Shi, W.; Qiu, Q.; Dai, Y.; Huang, W.; Qian, H. Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2. Bioorg. Med. Chem.,  2016, 24(16), 3353-3358.
[http://dx.doi.org/10.1016/j.bmc.2016.03.061] [PMID:  27068889] 
[76] 
Zhu, W.; Wang, W.; Xu, S.; Tang, Q.; Luo, R.; Wang, M.; Gong, P.; Zheng, P. Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors. Bioorg. Med. Chem.,  2016, 24, 812-819.
[http://dx.doi.org/[DOI: https://doi.org/10.1016/j.bmc.2016.01.001] 
[77] 
Liu, J.; Nie, M.; Wang, Y.; Hu, J.; Zhang, F.; Gao, Y.; Liu, Y.; Gong, P. Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. Eur. J. Med. Chem.,  2016, 123, 431-446.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.059] [PMID:  27490023] 
[78] 
Zhao, S.; Zhang, Y.; Zhou, H.; Xi, S.; Zou, B.; Bao, G.; Wang, L.; Wang, J.; Zeng, T.; Gong, P.; Zhai, X. Synthesis and biological evaluation of 4-(2-fluorophenoxy)-3,3′-bipyridine derivatives as potential c-met inhibitors. Eur. J. Med. Chem.,  2016, 120, 37-50.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.062] [PMID:  27187857] 
[79] 
Mohyeldin, M.M.; Busnena, B.A.; Akl, M.R.; Dragoi, A.M.; Cardelli, J.A.; El Sayed, K.A. Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer. Eur. J. Med. Chem.,  2016, 118, 299-315.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.043] [PMID:  27258622] 
[80] 
Mannion, M.; Raeppel, S.; Claridge, S.; Zhou, N.; Saavedra, O.; Isakovic, L.; Zhan, L.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.; Nguyen, H.; Chute, I.; Beaulieu, C.; Dupont, I.; Robert, M.F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Robert Macleod, A.; Besterman, J.M.; Vaisburg, A.N. -(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(23), 6552-6556.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.040] [PMID:  19854051] 
[81] 
Raeppel, S.; Claridge, S.; Saavedra, O.; Gaudette, F.; Zhan, L.; Mannion, M.; Zhou, N.; Raeppel, F.; Granger, M.C.; Isakovic, L.; Déziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Robert, M.F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Robert Macleod, A.; Besterman, J.; Vaisburg, A.N. -(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(5), 1323-1328.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.068] [PMID:  19211249] 
[82] 
Kim, K.S.; Zhang, L.; Schmidt, R.; Cai, Z.W.; Wei, D.; Williams, D.K.; Lombardo, L.J.; Trainor, G.L.; Xie, D.; Zhang, Y.; An, Y.; Sack, J.S.; Tokarski, J.S.; Darienzo, C.; Kamath, A.; Marathe, P.; Zhang, Y.; Lippy, J.; Jeyaseelan, R., Sr; Wautlet, B.; Henley, B.; Gullo-Brown, J.; Manne, V.; Hunt, J.T.; Fargnoli, J.; Borzilleri, R.M. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities. J. Med. Chem.,  2008, 51(17), 5330-5341.
[http://dx.doi.org/10.1021/jm800476q] [PMID:  18690676] 
[83] 
Schroeder, G.M.; An, Y.; Cai, Z.W.; Chen, X.T.; Clark, C.; Cornelius, L.A.M.; Dai, J.; Gullo-Brown, J.; Gupta, A.; Henley, B.; Hunt, J.T.; Jeyaseelan, R.; Kamath, A.; Kim, K.; Lippy, J.; Lombardo, L.J.; Manne, V.; Oppenheimer, S.; Sack, J.S.; Schmidt, R.J.; Shen, G.; Stefanski, K.; Tokarski, J.S.; Trainor, G.L.; Wautlet, B.S.; Wei, D.; Williams, D.K.; Zhang, Y.; Zhang, Y.; Fargnoli, J.; Borzilleri, R.M. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J. Med. Chem.,  2009, 52(5), 1251-1254.
[http://dx.doi.org/10.1021/jm801586s] [PMID:  19260711] 
[84] 
Smith, L.I.I.; Wong, W.C.; Kiselyov, A.S.; Burdzovic-Wizemann, S.; Mao, Y.; Xu, Y.; Duncton, M.A.; Kim, K.; Piatnitski, E.L.; Doody, J.F.; Wang, Y.; Rosler, R.L.; Milligan, D.; Columbus, J.; Balagtas, C.; Lee, S.P.; Konovalov, A.; Hadari, Y.R. Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase. Bioorg. Med. Chem. Lett.,  2006, 16(19), 5102-5106.
[http://dx.doi.org/10.1016/j.bmcl.2006.07.031] [PMID:  16887347] 
[85] 
Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science,  2002, 298(5600), 1912-1934.
[http://dx.doi.org/10.1126/science.1075762] [PMID:  12471243] 
[86] 
Bottaro, D.P.; Rubin, J.S.; Faletto, D.L.; Chan, A.M.; Kmiecik, T.E.; Vande Woude, G.F.; Aaronson, S.A. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science,  1991, 251(4995), 802-804.
[http://dx.doi.org/10.1126/science.1846706] [PMID:  1846706] 
[87] 
Giordano, S.; Ponzetto, C.; Di Renzo, M.F.; Cooper, C.S.; Comoglio, P.M. Tyrosine kinase receptor indistinguishable from the c-met protein. Nature,  1989, 339(6220), 155-156.
[http://dx.doi.org/10.1038/339155a0] [PMID:  2541345] 
[88] 
Dean, M.; Park, M.; Le Beau, M.M.; Robins, T.S.; Diaz, M.O.; Rowley, J.D.; Blair, D.G.; Vande Woude, G.F. The human met oncogene is related to the tyrosine kinase oncogenes. Nature,  1985, 318(6044), 385-388.
[http://dx.doi.org/10.1038/318385a0] [PMID:  4069211] 
[89] 
Ma, P.C.; Kijima, T.; Maulik, G.; Fox, E.A.; Sattler, M.; Griffin, J.D.; Johnson, B.E.; Salgia, R. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res.,  2003, 63(19), 6272-6281.
[PMID:  14559814] 
[90] 
Avan, A.; Maftouh, M.; Funel, N.; Ghayour-Mobarhan, M.; Boggi, U.; Peters, G.J.; Giovannetti, E. MET as a potential target for the treatment of upper gastrointestinal cancers: characterization of novel c-Met inhibitors from bench to bedside. Curr. Med. Chem.,  2014, 21(8), 975-989.
[http://dx.doi.org/10.2174/09298673113209990231] [PMID:  23992325] 
[91] 
Graff, J.R.; Konicek, B.W.; McNulty, A.M.; Wang, Z.; Houck, K.; Allen, S.; Paul, J.D.; Hbaiu, A.; Goode, R.G.; Sandusky, G.E.; Vessella, R.L.; Neubauer, B.L. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J. Biol. Chem.,  2000, 275(32), 24500-24505.
[http://dx.doi.org/10.1074/jbc.M003145200] [PMID:  10827191] 
[92] 
Christensen, J.G.; Burrows, J.; Salgia, R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett.,  2005, 225(1), 1-26.
[http://dx.doi.org/10.1016/j.canlet.2004.09.044] [PMID:  15922853] 
[93] 
Cappuzzo, F.; Marchetti, A.; Skokan, M.; Rossi, E.; Gajapathy, S.; Felicioni, L.; Del Grammastro, M.; Sciarrotta, M.G.; Buttitta, F.; Incarbone, M.; Toschi, L.; Finocchiaro, G.; Destro, A.; Terracciano, L.; Roncalli, M.; Alloisio, M.; Santoro, A.; Varella-Garcia, M. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J. Clin. Oncol.,  2009, 27(10), 1667-1674.
[http://dx.doi.org/10.1200/JCO.2008.19.1635] [PMID:  19255323] 
[94] 
Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A.D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.C.; Joly, A.H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther.,  2011, 10(12), 2298-2308.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0264] [PMID:  21926191] 
[95] 
D′Angelo, N.D.; Bellon, S.F.; Booker, S.K.; Cheng, Y.; Coxon, A.; Dominguez, C.; Fellows, I.; Hoffman, D.; Hungate, R.; Kaplan-Lefko, P.; Lee, M.R.; Li, C.; Liu, L.B.; Rainbeau, E.; Reider, P.J.; Rex, K.; Siegmund, A.; Sun, Y.X.; Tasker, A.S.; Xi, N.; Xu, S.M.; Yang, Y.J.; Zhang, Y.H.; Burgess, T.L.; Dussault, I.; Kim, T. Design, synthesis, and biological evaluation of potent c-Met inhibitors. J. Med. Chem.,  2008, 51, 5766-5779.
[96] 
Dorsch, D.; Schadt, O.; Stieber, F.; Meyring, M.; Grädler, U.; Bladt, F.; Friese-Hamim, M.; Knühl, C.; Pehl, U.; Blaukat, A. Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors. Bioorg. Med. Chem. Lett.,  2015, 25(7), 1597-1602.
[http://dx.doi.org/10.1016/j.bmcl.2015.02.002] [PMID:  25736998] 
[97] 
Nishii, H.; Chiba, T.; Morikami, K.; Fukami, T.A.; Sakamoto, H.; Ko, K.; Koyano, H. Discovery of 6-benzyloxyquinolines as c-Met selective kinase inhibitors. Bioorg. Med. Chem. Lett.,  2010, 20(4), 1405-1409.
[http://dx.doi.org/10.1016/j.bmcl.2009.12.109] [PMID:  20093027] 
[98] 
Wang, L.; Ai, J.; Shen, Y.; Zhang, H.; Peng, X.; Huang, M.; Zhang, A.; Ding, J.; Geng, M. SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo. Cancer Lett.,  2014, 351(1), 143-150.
[http://dx.doi.org/10.1016/j.canlet.2014.05.012] [PMID:  24880078] 
[99] 
Park, C.H.; Cho, S.Y.; Ha, J.D.; Jung, H.; Kim, H.R.; Lee, C.O.; Jang, I.Y.; Chae, C.H.; Lee, H.K.; Choi, S.U. Novel c-Met inhibitor suppresses the growth of c-Met-addicted gastric cancer cells. BMC Cancer,  2016, 16, 35.
[http://dx.doi.org/10.1186/s12885-016-2058-y] [PMID:  26801760] 
[100] 
Liu, X.; Wang, Q.; Yang, G.; Marando, C.; Koblish, H.K.; Hall, L.M.; Fridman, J.S.; Behshad, E.; Wynn, R.; Li, Y.; Boer, J.; Diamond, S.; He, C.; Xu, M.; Zhuo, J.; Yao, W.; Newton, R.C.; Scherle, P.A. A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin. Cancer Res.,  2011, 17(22), 7127-7138.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1157] [PMID:  21918175] 
[101] 
Burgess, T.; Coxon, A.; Meyer, S.; Sun, J.; Rex, K.; Tsuruda, T.; Chen, Q.; Ho, S.Y.; Li, L.; Kaufman, S.; McDorman, K.; Cattley, R.C.; Sun, J.; Elliott, G.; Zhang, K.; Feng, X.; Jia, X.C.; Green, L.; Radinsky, R.; Kendall, R. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res.,  2006, 66(3), 1721-1729.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3329] [PMID:  16452232] 
[102] 
Jin, H.; Yang, R.; Zheng, Z.; Romero, M.; Ross, J.; Bou-Reslan, H.; Carano, R.A.D.; Kasman, I.; Mai, E.; Young, J.; Zha, J.; Zhang, Z.; Ross, S.; Schwall, R.; Colbern, G.; Merchant, M. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res.,  2008, 68(11), 4360-4368.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5960] [PMID:  18519697] 
[103] 
van der Horst, E.H.; Chinn, L.; Wang, M.; Velilla, T.; Tran, H.; Madrona, Y.; Lam, A.; Ji, M.; Hoey, T.C.; Sato, A.K. Discovery of fully human anti-MET monoclonal antibodies with antitumor activity against colon cancer tumor models in vivo. Neoplasia,  2009, 11(4), 355-364.
[http://dx.doi.org/10.1593/neo.81536] [PMID:  19308290] 
[104] 
Liu, X.; Newton, R.C.; Scherle, P.A. Development of c-MET pathway inhibitors. Expert Opin. Investig. Drugs,  2011, 20(9), 1225-1241.
[http://dx.doi.org/10.1517/13543784.2011.600687] [PMID:  21740293] 
[105] 
Abidoye, O.; Murukurthy, N.; Salgia, R. Review of clinic trials: agents targeting c-Met. Rev. Recent Clin. Trials,  2007, 2(2), 143-147.
[http://dx.doi.org/10.2174/157488707780599357] [PMID:  18473999] 
[106] 
Shi, P.; Oh, Y.T.; Zhang, G.; Yao, W.; Yue, P.; Li, Y.; Kanteti, R.; Riehm, J.; Salgia, R.; Owonikoko, T.K.; Ramalingam, S.S.; Chen, M.; Sun, S.Y. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett.,  2016, 380(2), 494-504.
[http://dx.doi.org/10.1016/j.canlet.2016.07.021] [PMID:  27450722] 
[107] 
Cui, J.J.; Tran-Dubé, M.; Shen, H.; Nambu, M.; Kung, P.P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R.S.; Edwards, M.P. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem.,  2011, 54(18), 6342-6363.
[http://dx.doi.org/10.1021/jm2007613] [PMID:  21812414] 
[108] 
Roy, S.; Narang, B.K.; Rastogi, S.K.; Rawal, R.K. A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib. Anticancer. Agents Med. Chem.,  2015, 15(1), 37-47.
[http://dx.doi.org/10.2174/1871520614666140902153840] [PMID:  25181996] 
[109] 
Cui, J.J.; McTigue, M.; Nambu, M.; Tran-Dubé, M.; Pairish, M.; Shen, H.; Jia, L.; Cheng, H.; Hoffman, J.; Le, P.; Jalaie, M.; Goetz, G.H.; Ryan, K.; Grodsky, N.; Deng, Y.L.; Parker, M.; Timofeevski, S.; Murray, B.W.; Yamazaki, S.; Aguirre, S.; Li, Q.; Zou, H.; Christensen, J. Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer. J. Med. Chem.,  2012, 55(18), 8091-8109.
[http://dx.doi.org/10.1021/jm300967g] [PMID:  22924734] 
[110] 
Martens, T.; Schmidt, N.O.; Eckerich, C.; Fillbrandt, R.; Merchant, M.; Schwall, R.; Westphal, M.; Lamszus, K. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin. Cancer Res.,  2006, 12(20 Pt 1), 6144-6152.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1418] [PMID:  17062691] 
[111] 
Kim, S.J.; Johnson, M.; Koterba, K.; Herynk, M.H.; Uehara, H.; Gallick, G.E. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin. Cancer Res.,  2003, 9(14), 5161-5170.
[PMID:  14613995] 
[112] 
Liu, X.; Wang, Q.; Yang, G.; Marando, C.; Koblish, H.K.; Hall, L.M.; Fridman, J.S.; Behshad, E.; Wynn, R.; Li, Y.; Boer, J.; Diamond, S.; He, C.; Xu, M.; Zhuo, J.; Yao, W.; Newton, R.C.; Scherle, P.A. A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin. Cancer Res.,  2011, 17(22), 7127-7138.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1157] [PMID:  21918175] 
[113] 
Boezio, A.A.; Copeland, K.W.; Rex, K.; K, Albrecht. B.; Bauer, D.; Bellon, S.F.; Boezio, C.; Broome, M.A.; Choquette, D.; Coxon, A.; Dussault, I.; Hirai, S.; Lewis, R.; Lin, M.H.; Lohman, J.; Liu, J.; Peterson, E.A.; Potashman, M.; Shimanovich, R.; Teffera, Y.; Whittington, D.A.; Vaida, K.R.; Harmange, J.C. Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity. J. Med. Chem.,  2016, 59(6), 2328-2342.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01716] [PMID:  26812066] 
[114] 
Hughes, P.E.; Rex, K.; Caenepeel, S.; Yang, Y.; Zhang, Y.; Broome, M.A.; Kha, H.T.; Burgess, T.L.; Amore, B.; Kaplan-Lefko, P.J.; Moriguchi, J.; Werner, J.; Damore, M.A.; Baker, D.; Choquette, D.M.; Harmange, J.C.; Radinsky, R.; Kendall, R.; Dussault, I.; Coxon, A. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. Mol. Cancer Ther.,  2016, 15(7), 1568-1579.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0871] [PMID:  27196782] 
[115] 
Elisei, R.; Schlumberger, M.J.; Müller, S.P.; Schöffski, P.; Brose, M.S.; Shah, M.H.; Licitra, L.; Jarzab, B.; Medvedev, V.; Kreissl, M.C.; Niederle, B.; Cohen, E.E.W.; Wirth, L.J.; Ali, H.; Hessel, C.; Yaron, Y.; Ball, D.; Nelkin, B.; Sherman, S.I. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol.,  2013, 31(29), 3639-3646.
[http://dx.doi.org/10.1200/JCO.2012.48.4659] [PMID:  24002501] 
[116] 
Liu, L.; Siegmund, A.; Xi, N.; Kaplan-Lefko, P.; Rex, K.; Chen, A.; Lin, J.; Moriguchi, J.; Berry, L.; Huang, L.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S.F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.; Norman, M.H.; Harmange, J.C.; Dussault, I.; Kim, T.S. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458). J. Med. Chem.,  2008, 51(13), 3688-3691.
[http://dx.doi.org/10.1021/jm800401t] [PMID:  18553959] 
[117] 
Sattler, M.; Pride, Y.B.; Ma, P.; Gramlich, J.L.; Chu, S.C.; Quinnan, L.A.; Shirazian, S.; Liang, C.; Podar, K.; Christensen, J.G.; Salgia, R. A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res.,  2003, 63(17), 5462-5469.
[PMID:  14500382] 
[118] 
Christensen, J.G.; Schreck, R.; Burrows, J.; Kuruganti, P.; Chan, E.; Le, P.; Chen, J.; Wang, X.; Ruslim, L.; Blake, R.; Lipson, K.E.; Ramphal, J.; Do, S.; Cui, J.J.; Cherrington, J.M.; Mendel, D.B. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res.,  2003, 63(21), 7345-7355.
[PMID:  14612533] 
[119] 
Cui, J.J. Inhibitors targeting hepatocyte growth factor receptor and their potential therapeutic applications. Expert Opin. Ther. Pat.,  2007, 17, 1035-1045.
[http://dx.doi.org/10.1517/13543776.17.9.1035] 
[120] 
Zillhardt, M.; Christensen, J.G.; Lengyel, E. An orally available small-molecule inhibitor of c-Met, PF-2341066, reduces tumor burden and metastasis in a preclinical model of ovarian cancer metastasis. Neoplasia,  2010, 12(1), 1-10.
[http://dx.doi.org/10.1593/neo.09948] [PMID:  20072648] 
[121] 
Albrecht, B.K.; Harmange, J.C.; Bauer, D.; Berry, L.; Bode, C.; Boezio, A.A.; Chen, A.; Choquette, D.; Dussault, I.; Fridrich, C.; Hirai, S.; Hoffman, D.; Larrow, J.F.; Kaplan-Lefko, P.; Lin, J.; Lohman, J.; Long, A.M.; Moriguchi, J.; O’Connor, A.; Potashman, M.H.; Reese, M.; Rex, K.; Siegmund, A.; Shah, K.; Shimanovich, R.; Springer, S.K.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S.F. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. J. Med. Chem.,  2008, 51(10), 2879-2882.
[http://dx.doi.org/10.1021/jm800043g] [PMID:  18426196] 
[122] 
Sattler, M.; Salgia, R. c-Met and hepatocyte growth factor: Potential as novel targets in cancer therapy. Curr. Oncol. Rep.,  2007, 9(2), 102-108.
[http://dx.doi.org/10.1007/s11912-007-0005-4] [PMID:  17288874] 
[123] 
Corso, S.; Comoglio, P.M.; Giordano, S. Cancer therapy: can the challenge be MET? Trends Mol. Med.,  2005, 11(6), 284-292.
[http://dx.doi.org/10.1016/j.molmed.2005.04.005] [PMID:  15949770] 
[124] 
Matsumoto, K.; Nakamura, T. NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci.,  2003, 94(4), 321-327.
[http://dx.doi.org/10.1111/j.1349-7006.2003.tb01440.x] [PMID:  12824898] 
[125] 
Trusolino, L.; Comoglio, P.M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer,  2002, 2(4), 289-300.
[http://dx.doi.org/10.1038/nrc779] [PMID:  12001990] 
[126] 
Cui, J.J. Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress. J. Med. Chem.,  2014, 57(11), 4427-4453.
[http://dx.doi.org/10.1021/jm401427c] [PMID:  24320965] 
[127] 
Liao, W.; Xu, C.; Ji, X.; Hu, G.; Ren, L.; Liu, Y.; Li, R.; Gong, P.; Sun, T. Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors. Eur. J. Med. Chem.,  2014, 87, 508-518.
[http://dx.doi.org/10.1016/j.ejmech.2014.09.095] [PMID:  25282672] 
[128] 
Zhang, W.; Ai, J.; Shi, D.; Peng, X.; Ji, Y.; Liu, J.; Geng, M.; Li, Y. Discovery of novel type II c-Met inhibitors based on BMS-777607. Eur. J. Med. Chem.,  2014, 80, 254-266.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.056] [PMID:  24792774] 
[129] 
Liu, Y.; Jin, S.; Peng, X.; Lu, D.; Zeng, L.; Sun, Y.; Ai, J.; Geng, M.; Hu, Y. Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase. Eur. J. Med. Chem.,  2016, 108, 322-333.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.042] [PMID:  26698536] 
[130] 
Li, S.; Zhao, Y.; Wang, K.; Gao, Y.; Han, J.; Cui, B.; Gong, P. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg. Med. Chem.,  2013, 21(11), 2843-2855.
[http://dx.doi.org/10.1016/j.bmc.2013.04.013] [PMID:  23628470] 
[131] 
Shi, L.; Wu, T.T.; Wang, Z.; Xue, J.Y.; Xu, Y.G. Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2. Bioorg. Med. Chem.,  2014, 22(17), 4735-4744.
[http://dx.doi.org/10.1016/j.bmc.2014.07.008] [PMID:  25082515] 
[132] 
Li, S.; Huang, Q.; Liu, Y.; Zhang, X.; Liu, S.; He, C.; Gong, P. Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety. Eur. J. Med. Chem.,  2013, 64, 62-73.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.001] [PMID:  23644189] 
[133] 
Liao, Y.; Grobholz, R.; Abel, U.; Trojan, L.; Michel, M.S.; Angel, P.; Mayer, D. Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer. Int. J. Cancer,  2003, 107(4), 676-680.
[http://dx.doi.org/10.1002/ijc.11471] [PMID:  14520710] 
[134] 
Kreisberg, J.I.; Malik, S.N.; Prihoda, T.J.; Bedolla, R.G.; Troyer, D.A.; Kreisberg, S.; Ghosh, P.M. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res.,  2004, 64(15), 5232-5236.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0272] [PMID:  15289328] 
[135] 
You, W.K.; Sennino, B.; Williamson, C.W.; Falcón, B.; Hashizume, H.; Yao, L.C.; Aftab, D.T.; McDonald, D.M. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res.,  2011, 71(14), 4758-4768.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2527] [PMID:  21613405] 
[136] 
Chandrappa, S.; Vinaya, K.; Ramakrishnappa, T.; Rangappa, K.S. An efficient method for aryl nitro reduction and cleavage of azo compounds using iron powder/calcium chloride. Synlett,  2010, 20, 3019-3022.
[http://dx.doi.org/[DOI: 10.1055/s-0030-1259067] 
[137] 
Liu, Y.; Jin, S.; Peng, X.; Lu, D.; Zeng, L.; Sun, Y.; Ai, J.; Geng, M.; Hu, Y. Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase. Eur. J. Med. Chem.,  2016, 108, 322-333.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.042] [PMID:  26698536] 
[138] 
Zhang, W.; Zhang, D.; Stashko, M.A.; DeRyckere, D.; Hunter, D.; Kireev, D.; Miley, M.J.; Cummings, C.; Lee, M.; Norris-Drouin, J.; Stewart, W.M.; Sather, S.; Zhou, Y.; Kirkpatrick, G.; Machius, M.; Janzen, W.P.; Earp, H.S.; Graham, D.K.; Frye, S.V.; Wang, X. Pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new Mer kinase inhibitors. J. Med. Chem.,  2013, 56(23), 9683-9692.
[http://dx.doi.org/10.1021/jm401387j] [PMID:  24195762] 
[139] 
Kataoka, Y.; Mukohara, T.; Tomioka, H.; Funakoshi, Y.; Kiyota, N.; Fujiwara, Y.; Yashiro, M.; Hirakawa, K.; Hirai, M.; Minami, H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest. New Drugs,  2012, 30(4), 1352-1360.
[http://dx.doi.org/10.1007/s10637-011-9699-0] [PMID:  21655918] 
[140] 
Tiedt, R.; Degenkolbe, E.; Furet, P.; Appleton, B.A.; Wagner, S.; Schoepfer, J.; Buck, E.; Ruddy, D.A.; Monahan, J.E.; Jones, M.D.; Blank, J.; Haasen, D.; Drueckes, P.; Wartmann, M.; McCarthy, C.; Sellers, W.R.; Hofmann, F. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res.,  2011, 71(15), 5255-5264.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-4433] [PMID:  21697284] 
[141] 
Li, S.; Zhao, Y.; Wang, K.; Gao, Y.; Han, J.; Cui, B.; Gong, P. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg. Med. Chem.,  2013, 21(11), 2843-2855.
[http://dx.doi.org/10.1016/j.bmc.2013.04.013] [PMID:  23628470] 
[142] 
Li, S.; Huang, Q.; Liu, Y.; Zhang, X.; Liu, S.; He, C.; Gong, P. Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety. Eur. J. Med. Chem.,  2013, 64, 62-73.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.001] [PMID:  23644189] 
[143] 
Porter, J. Small molecule c-Met kinase inhibitors: A review of recent patents. Expert Opin. Ther. Pat.,  2010, 20, 159-177.
[http://dx.doi.org/10.1517/13543770903514137] 
[144] 
Norman, M.H.; Liu, L.; Lee, M.; Xi, N.; Fellows, I.; D’Angelo, N.D.; Dominguez, C.; Rex, K.; Bellon, S.F.; Kim, T.S.; Dussault, I. Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives. J. Med. Chem.,  2012, 55(5), 1858-1867.
[http://dx.doi.org/10.1021/jm201330u] [PMID:  22320343] 
[145] 
Liu, L.; Norman, M.H.; Lee, M.; Xi, N.; Siegmund, A.; Boezio, A.A.; Booker, S.; Choquette, D.; D’Angelo, N.D.; Germain, J.; Yang, K.; Yang, Y.; Zhang, Y.; Bellon, S.F.; Whittington, D.A.; Harmange, J.C.; Dominguez, C.; Kim, T.S.; Dussault, I. Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series. J. Med. Chem.,  2012, 55(5), 1868-1897.
[http://dx.doi.org/10.1021/jm201331s] [PMID:  22320327] 
[146] 
Bellon, S.F.; Kaplan-Lefko, P.; Yang, Y.; Zhang, Y.; Moriguchi, J.; Rex, K.; Johnson, C.W.; Rose, P.E.; Long, A.M.; O’Connor, A.B.; Gu, Y.; Coxon, A.; Kim, T.S.; Tasker, A.; Burgess, T.L.; Dussault, I. c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J. Biol. Chem.,  2008, 283(5), 2675-2683.
[http://dx.doi.org/10.1074/jbc.M705774200] [PMID:  18055465] 
[147] 
Zillhardt, M.; Park, S.M.; Romero, I.L.; Sawada, K.; Montag, A.; Krausz, T.; Yamada, S.D.; Peter, M.E.; Lengyel, E. Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin. Cancer Res.,  2011, 17(12), 4042-4051.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-3387] [PMID:  21551255] 
[148] 
Jia, H.; Dai, G.; Weng, J.; Zhang, Z.; Wang, Q.; Zhou, F.; Jiao, L.; Cui, Y.; Ren, Y.; Fan, S.; Zhou, J.; Qing, W.; Gu, Y.; Wang, J.; Sai, Y.; Su, W. Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. J. Med. Chem.,  2014, 57(18), 7577-7589.
[http://dx.doi.org/10.1021/jm500510f] [PMID:  25148209] 
[149] 
Cui, J.J.; Tran-Dubé, M.; Shen, H.; Nambu, M.; Kung, P.P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R.S.; Edwards, M.P. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J. Med. Chem.,  2011, 54(18), 6342-6363.
[http://dx.doi.org/10.1021/jm2007613] [PMID:  21812414] 
[150] 
You, W.K.; Sennino, B.; Williamson, C.W.; Falcón, B.; Hashizume, H.; Yao, L.C.; Aftab, D.T.; McDonald, D.M. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res.,  2011, 71(14), 4758-4768.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2527] [PMID:  21613405] 
[151] 
Xing, W.; Ai, J.; Jin, S.; Shi, Z.; Peng, X.; Wang, L.; Ji, Y.; Lu, D.; Liu, Y.; Geng, M.; Hu, Y. Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis. Eur. J. Med. Chem.,  2015, 95, 302-312.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.041] [PMID:  25827399] 
[152] 
Tang, Q.; Zhao, Y.; Du, X.; Chong, L.; Gong, P.; Guo, C. Design, synthesis, and structure-activity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents. Eur. J. Med. Chem.,  2013, 69, 77-89.
[http://dx.doi.org/10.1016/j.ejmech.2013.08.019] [PMID:  24012712] 
[153] 
Li, S.; Jiang, R.; Qin, M.; Liu, H.; Zhang, G.; Gong, P. Synthesis and antitumor activity of novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline-3-carboxamide moiety. Arch. Pharm. (Weinheim),  2013, 346(7), 521-533.
[http://dx.doi.org/10.1002/ardp.201300029] [PMID:  23776085] 
[154] 
Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X. Synthesis of tricyclic 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. Org. Lett.,  2005, 7(8), 1541-1543.
[http://dx.doi.org/10.1021/ol050181f] [PMID:  15816747] 
[155] 
Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A.D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.C.; Joly, A.H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther.,  2011, 10(12), 2298-2308.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0264] [PMID:  21926191] 
[156] 
Winters, G.; Sala, A.; Barone, D.; Baldoli, E. Synthesis, in vitro [3H]prazosin displacement, and in vivo activity of 3-aryl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridines, a new class of antihypertensive agents. J. Med. Chem.,  1985, 28(7), 934-940.
[http://dx.doi.org/10.1021/jm00145a015] [PMID:  2989524] 
[157] 
Wang, Y.; Ai, J.; Wang, Y.; Chen, Y.; Wang, L.; Liu, G.; Geng, M.; Zhang, A. Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent. J. Med. Chem.,  2011, 54(7), 2127-2142.
[http://dx.doi.org/10.1021/jm101340q] [PMID:  21405128] 
[158] 
Liu, J.; Nie, M.; Wang, Y.; Hu, J.; Zhang, F.; Gao, Y.; Liu, Y.; Gong, P. Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. Eur. J. Med. Chem.,  2016, 123, 431-446.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.059] [PMID:  27490023] 
[159] 
Kovač, T.; Oklobdžija, M.; Comisso, G.; Decorte, E.; Fajdiga, T.; Moimas, F.; Anglli, C.; Zonno, F.; Toso, R.; Šunjić, V. A new synthesis of symmetrical 2,5‐diaryl‐1,3,4‐thiadiazoles. J. Heterocycl. Chem.,  1983, 20, 1339-1349.
[http://dx.doi.org/[DOI: https://doi.org/10.1002/jhet.5570200547] 
[160] 
Wang, H.C.; Jagtap, A.D.; Chang, P.T.; Liu, J.R.; Liu, C.P.; Tseng, H.W.; Chen, G.S.; Chern, J.W. Bioisosteric replacement of an acylureido moiety attached to an indolin-2-one scaffold with a malonamido or a 2/4-pyridinoylamido moiety produces a selectively potent Aurora-B inhibitor. Eur. J. Med. Chem.,  2014, 84, 312-334.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.033] [PMID:  25036791] 
[161] 
Zheng, Y.Y.; Weng, Z.J.; Xie, P.; Zhu, M.Y.; Xing, L.X.; Li, J.Q. Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple reuptake inhibitors. Eur. J. Med. Chem.,  2014, 86, 219-234.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.045] [PMID:  25164761] 
[162] 
Cui, J.J.; Shen, H.; Tran-Dubé, M.; Nambu, M.; McTigue, M.; Grodsky, N.; Ryan, K.; Yamazaki, S.; Aguirre, S.; Parker, M.; Li, Q.; Zou, H.; Christensen, J. Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats. J. Med. Chem.,  2013, 56(17), 6651-6665.
[http://dx.doi.org/10.1021/jm400926x] [PMID:  23944843] 
[163] 
Zou, H.Y.; Li, Q.; Lee, J.H.; Arango, M.E.; McDonnell, S.R.; Yamazaki, S.; Koudriakova, T.B.; Alton, G.; Cui, J.J.; Kung, P.P.; Nambu, M.D.; Los, G.; Bender, S.L.; Mroczkowski, B.; Christensen, J.G. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res.,  2007, 67(9), 4408-4417.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4443] [PMID:  17483355] 
[164] 
Peters, S.; Adjei, A.A. MET: A promising anticancer therapeutic target. Nat. Rev. Clin. Oncol.,  2012, 9(6), 314-326.
[http://dx.doi.org/10.1038/nrclinonc.2012.71] [PMID:  22566105] 
[165] 
Ma, Y.; Sun, G.; Chen, D.; Peng, X.; Chen, Y.L.; Su, Y.; Ji, Y.; Liang, J.; Wang, X.; Chen, L.; Ding, J.; Xiong, B.; Ai, J.; Geng, M.; Shen, J. Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors. J. Med. Chem.,  2015, 58(5), 2513-2529.
[http://dx.doi.org/10.1021/jm502018y] [PMID:  25668160] 
[166] 
Shi, W.; Qiang, H.; Huang, D.; Bi, X.; Huang, W.; Qian, H. Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2. Eur. J. Med. Chem.,  2018, 158, 814-831.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.050] [PMID:  30248654] 
[167] 
Tang, Q.; Duan, Y.; Xiong, H.; Chen, T.; Xiao, Z.; Wang, L.; Xiao, Y.; Huang, S.; Xiong, Y.; Zhu, W.; Gong, P.; Zheng, P. Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety. Eur. J. Med. Chem.,  2018, 158, 201-213.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.066] [PMID:  30216852] 
[168] 
Tang, Q.; Duan, Y.; Wang, L.; Wang, M.; Ouyang, Y.; Wang, C.; Mei, H.; Tang, S.; Xiong, Y.; Zheng, P.; Gong, P.; Tang, Q.; Duan, Y.; Wang, L.; Wang, M.; Ouyang, Y.; Wang, C.; Mei, H.; Tang, S.; Xiong, Y.; Zheng, P.; Gong, P.; Zhu, W. Synthesis and antiproliferative activity of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety. Eur. J. Med. Chem.,  2018, 143, 266-275.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.034] [PMID:  29197731] 
[169] 
Qi, B.; Yang, Y.; He, H.; Yue, X.; Zhou, Y.; Zhou, X.; Chen, Y.; Liu, M.; Zhang, A.; Wei, F. Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities. Eur. J. Med. Chem.,  2018, 146, 368-380.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.061] [PMID:  29407963] 
[170] 
Zhang, L.; Zhao, J.; Zhang, B.; Lu, T.; Chen, Y. Discovery of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as novel, potent and selective c-Met kinase inhibitors: Synthesis, SAR study, and biological activity. Eur. J. Med. Chem.,  2018, 150, 809-816.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.049] [PMID:  29602036] 
[171] 
Nan, X.; Jiang, Y.F.; Li, H.J.; Wang, J.H.; Wu, Y.C. Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors. Bioorg. Med. Chem.,  2019, 27(13), 2801-2812.
[http://dx.doi.org/10.1016/j.bmc.2019.05.007] [PMID:  31079967] 
Rights & Permissions Print Cite
Article Metrics
92
11
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568026619666190712205353	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Recent Progress in the Development of Small Molecule c-Met Inhibitors

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
