The MET receptor tyrosine kinase (RTK) plays a central role in regulating cell growth, survival, and invasion. Binding of hepatocyte growth factor (HGF) promotes MET dimerization, stimulating MET kinase activity. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. It potently inhibits the enzymatic activity of WT MET (IC50 = 1 nM) and a subset of MET mutants found in papillary renal cell carcinoma. AMG 337 also inhibits cell based HGF-induced MET phosphorylation in PC3 cells (IC50 = 5 nM). Competitive binding assays illustrated the selectivity of AMG 337, binding only MET when profiled against a diverse panel of 402 human kinases. AMG 337 inhibits proliferation in MET-dependent cancer cell lines following 72 hours of treatment with AMG 337. MET phosphorylation was completely inhibited in the gastric cancer cells lines MKN-45, SNU-620, and SNU-5 cells, following a 2-hour treatment with 100 nM AMG 337. In MKN-45 cells, 300 nM AMG 337 treatment for 24 hours resulted in a dose-dependent increase in cells in the G1 phase; with concurrent reduction of cells in S-phase. AMG 337 at a 0.5 mg/kg dose robustly inhibited Gab-1 (a kind of adaptor protein) phosphorylation, and escalation to 0.75 mg/kg or more resulted in >90% inhibition of MET signaling in the TPR-MET mouse tumor model [3].
作用机制
AMG 337 binds to a well-defined, inactive conformation of the MET activation loop (A-loop) in a binding mode .
搜索
