2. Academic Validation
  3. SOMG-833, a novel selective c-MET inhibitor, blocks c-MET-dependent neoplastic effects and exerts antitumor activity

SOMG-833, a novel selective c-MET inhibitor, blocks c-MET-dependent neoplastic effects and exerts antitumor activity

  • J Pharmacol Exp Ther. 2014 Jul;350(1):36-45. doi: 10.1124/jpet.114.214817.
Hao-tian Zhang 1,  Lu Wang 1,  Jing Ai 1,  Yi Chen 1,  Chang-xi He 1,  Yin-chun Ji 1,  Min Huang 1,  Jing-yu Yang 1,  Ao Zhang 1,  Jian Ding 1,  Mei-yu Geng 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People's Republic of China (H.-t.Z., J.-y.Y.); Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (L.W., J.A., Y.C., C.-x.H., Y.-c.J., M.H., J.D., M.-y.G.) and CAS Key Laboratory of Receptor Research and Synthetic Organic & Medicinal Chemistry Laboratory (A.Z.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People's Republic of China (H.-t.Z., J.-y.Y.); Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (L.W., J.A., Y.C., C.-x.H., Y.-c.J., M.H., J.D., M.-y.G.) and CAS Key Laboratory of Receptor Research and Synthetic Organic & Medicinal Chemistry Laboratory (A.Z.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China [email protected] [email protected].
PMID: 24741075 DOI: 10.1124/jpet.114.214817
Abstract

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.

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