AMG 337

Description: AMG-337 is a novel, potent and highly selective small molecule ATP-competitive MET kinase inhibitor. In enzymatic assays, AMG 337 inhibited MET kinase activity with an IC50 of < 5nM nM. AMG 337 demonstrated exquisite selectivity for MET when profiled against a diverse panel of over 400 protein and lipid kinases in a competitive binding assay. In cellular assays, AMG 337 inhibited HGF-dependent MET phosphorylation with an IC50 of < 10 nM. To identify predictive genomic markers of response, AMG 337 was profiled in cell viability assays using a diverse panel of over 200 cancer cell lines. Treatment with AMG 337 only affected the viability of two gastric cancer cell lines (SNU-5 and Hs746T), both of which harbor amplification of the MET gene. The AMG 337 IC50 in the two sensitive cell lines was < 50 nM, and > 10 uM in all other tested cell lines. In vivo, oral administration of AMG 337 resulted in robust dose-dependent anti-tumor efficacy in MET amplified gastric cancer xenograft models, with inhibition of tumor growth consistent with the pharmacodynamic modulation of MET signaling. In conclusion, these findings illustrate the potential clinical utility of AMG 337 as a therapeutic agent for the treatment of tumors with evidence of dysregulated MET signaling, including MET amplification. A phase 1 clinical study is currently evaluating the safety, tolerability and pharmacokinectics of AMG 337 in patients with solid tumors.

References: Cancer Res October 1, 2014 74; 728; Expert Opin Ther Targets. 2012 Jun; 16(6):553-572.