AMG-208

AMG-208 is a potent, small-molecule c-Met inhibitor with IC50 of 5.2 nM against wt MET kinase, also inhibits VEGFR2 with IC50 of 112 nM; inhibits HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM, suppresses proliferation and induces apoptosis in human tumor xenograft models.Prostate Cancer Phase 2 Clinical (In Vitro) :AMG-208 (compound 4) treatment also leads to the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM.Pre-incubation of AMG-208 (compound 1) with human liver microsomes for 30 minutes shows a potent time-dependent inhibition for CYP3A4 metabolic activity with IC50 of 4.1 μM, which is an eightfold decrease relative to the IC50 (32 μM) without preincubation. (In Vivo) :In male Sprague Dawley rats, AMG-208 (0.5 mg/kg i.v.) shows a high bioavailability with Cl of 0.37 L/h/kg, Vss of 0.38 L/kg and T1/2 of 1 hour.