The hepatocyte growth factor/c-MET signaling axis is an attractive target for cancer therapy. 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. In contrast, SOMG-833 [(3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl) quinoline)] is a potent and selective c-MET inhibitor, with an IC50 of 0.93 nM against c-MET. This is over 10,000-fold more potent compared with 19 tyrosine kinases, including c-MET family members and highly homologous kinases. In a panel of 24 human cancer or genetically engineered model cell lines, SOMG-833 potently inhibited c-MET–driven cell proliferation. In addition, inhibition of primary human umbilical vascular endothelial cell proliferation and downregulation of plasma proangiogenic factor interleukin-8 secretion demonstrated potential antiangiogenic properties. These in vitro attributes led to remarkable antitumor efficacy in vivo, as demonstrated in NIH-3T3/TPR-MET, U-87MG, and EBC-1 xenograft models.
See article at J Pharmacol Exp Ther 2014, 350:36–45.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics