Abstract 728: AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models

Abstract

Abstract Signaling through the MET receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), promotes cell proliferation, survival, and invasion. Activation of MET signaling is a relatively common hallmark of a diverse range of human cancer types, and as a result, inhibition of MET signaling represents an attractive therapeutic opportunity for the treatment of cancer. In this study, we describe the characterization of AMG 337, a potent and highly selective small molecule ATP-competitive MET kinase inhibitor that demonstrates robust activity in MET-dependent cancer models. 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 μM in all other tested cell lines. Further studies in an expanded panel of additional cancer cell lines derived from gastric, NSCLC, and esophageal cancer confirmed that the in-vitro anti-proliferative activity of AMG 337 correlated with amplification of MET. In those cell lines, treatment with AMG 337 inhibited downstream PI3K and MAPK signaling pathways, which translated into growth arrest as evidenced by an accumulation of cells in the G1 phase of the cell cycle, a concomitant reduction in DNA synthesis, and the induction of apoptosis. 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. Citation Format: Paul E. Hughes, Yajing Yang, Karen Rex, Yihong Zhang, Paula J. Kaplan-Lefko, Sean Caenepeel, Jodi Moriguchi, Martin Broome, Deborah Choquette, Robert Radinsky, Richard Kendall, Angela Coxon, Isabelle Dussault. AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 728. doi:10.1158/1538-7445.AM2014-728