AMG 337 potently inhibits the enzymatic activity of WT MET and a subset of MET mutants found in papillary renal cell carcinoma. The inability of AMG 337 to inhibit the Y1230 and D1228 mutants is likely the result of a disruption of the inactive confirmation of the activation loop in the MET kinase domain. AMG 337 also inhibits cell based HGF-induced MET phosphorylation in PC3 cells with IC50 of 5nM.AMG 337 inhibits proliferation in MET-dependent cancer cell lines. AMG 337 inhibits signaling through the PI3K and MAPK pathways in MET-amplified gastric cancer cell lines resulting in profound effects on cell proliferation and survival.
In vivo
AMG 337 exhibits impressive potency with >90% inhibition of Gab-1 phosphorylation at a dose of 0.75 mg/kg (32 nmol/L free-drug concentration). AMG 337 is well tolerated at continuously administered doses that corresponded with complete MET inhibition for 24 hours, suggesting that AMG 337 has the preclinical attributes required to test the role of MET in human cancer.
Cell Research(from reference)
Cell lines：Human cancer cell lines
Concentrations：serial dilution(a top concentration of 3 mmol/L.)
1.Boezio AA, Berry L, Albrecht BK, Bauer D, Bellon SF, Bode C, Chen A, Choquette D, Dussault I, Fang M et al.. (2009) Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.. Bioorg Med Chem Lett, 19 (22):(6307-12). [PMID:19819693]
2.Bode CM, Boezio AA, Albrecht BK, Bellon SF, Berry L, Broome MA, Choquette D, Dussault I, Lewis RT, Lin MH et al.. (2012) Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.. Bioorg Med Chem Lett, 22 (12):(4089-93). [PMID:22595176]
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I2217159