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

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.

• Authors: Hao-tian Zhang, Lu Wang, Jing Ai, Yi Chen, Chang-xi He, Yin-chun Ji, Min Huang, Jing-yu Yang, Ao Zhang, Jian Ding, Mei-yu Geng
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 350 Issue 1 Pg. 36-45 (Jul 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 24741075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl)quinoline
• Aminoquinolines
• Antineoplastic Agents
• Interleukin-8
• Piperazines
• MET protein, human
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-met

Topics

• Aminoquinolines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dogs
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Interleukin-8 (drug effects, metabolism)
• Mice
• Piperazines (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors)
• Signal Transduction (drug effects)