RT Journal Article
SR Electronic
T1 SOMG-833, a Novel Selective c-MET Inhibitor, Blocks c-MET–Dependent Neoplastic Effects and Exerts Antitumor Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 36
OP 45
DO 10.1124/jpet.114.214817
VO 350
IS 1
A1 Zhang, Hao-tian
A1 Wang, Lu
A1 Ai, Jing
A1 Chen, Yi
A1 He, Chang-xi
A1 Ji, Yin-chun
A1 Huang, Min
A1 Yang, Jing-yu
A1 Zhang, Ao
A1 Ding, Jian
A1 Geng, Mei-yu
YR 2014
UL http://jpet.aspetjournals.org/content/350/1/36.abstract
AB The hepatocyte growth factor/c-MET signaling axis plays an important role in tumor cell proliferation, metastasis, and tumor angiogenesis, and therefore presents as an attractive target for cancer therapy. Notably, most small-molecule c-MET inhibitors currently undergoing clinical trials are multitarget inhibitors with the unwanted inhibition of additional kinases, often accounting for undesirable toxicity. Here, we discovered SOMG-833 [3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl) quinoline] as a potent and selective small-molecule c-MET inhibitor, with an average IC50 of 0.93 nM against c-MET, over 10,000-fold more potent compared with 19 tyrosine kinases, including c-MET family members and highly homologous kinases. SOMG-833 strongly suppressed c-MET–mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation, including MET gene amplification, MET gene fusion, and HGF-stimulated c-MET activation. In a panel of 24 human cancer or genetically engineered model cell lines, SOMG-833 potently inhibited c-MET–driven cell proliferation, whereas cancer cells lacking c-MET activation were markedly less sensitive (at least 15-fold) to the treatment. SOMG-833 also suppressed c-MET–mediated migration, invasion, urokinase activity, and invasive growth phenotype. In addition, inhibition of primary human umbilical vascular endothelial cell (HUVEC) proliferation and downregulation of plasma proangiogenic factor interleukin-8 secretion resulted from SOMG-833 treatment, suggesting its significant antiangiogenic properties. Together, these results led to the remarkable antitumor efficacy of SOMG-833 in vivo, as demonstrated in c-MET–dependent NIH-3T3/TPR-MET, U-87MG, and EBC-1 xenograft models. Collectively, our results suggested SOMG-833 as a promising candidate for highly selective c-MET inhibition and a powerful tool to investigate the sole role of MET kinase in cancer.