AMG-458

AMG-458 is a potent, selective and orally bioavailable c-Met inhibitor, with Ki values of 1.2 nM and 2.0 nM for human and mouse c-Met, respectively[1].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Met/HGFR

human c-Met:1.2 nM (Ki)

mouse c-Met:2.0 nM (Ki)

V1092I:1.1 nM (Ki)

D1228H:2.2 nM (Ki)

M1250T:4.1 nM (Ki)

H1094R:0.5 nM (Ki)

Y1230H:4.5 nM (Ki)

VEGDR2:4100 nM (Ki)

AMG-458 (orally, 30, 100 mg/kg) significantly inhibits tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight[1]. Animal Model: NIH-3T3/TPR-Met model and U-87 MG human glioblastoma xenograft model[1]. Dosage: 10, 30, 100 mg/kg. Administration: Orally q.d. or b.i.d. Result: With an ED50 of ∼12 mg/kg and an ED90 of ∼ 34 mg/kg in NIH-3T3/TPR-Met model. With an ED50 of ∼16 mg/kg and an ED90 of ∼ 59 mg/kg in U-87 MG human glioblastoma xenograft model. Significantly inhibited tumor growth at 30 and 100 mg/kg q.d. and 30 mg/kg b.i.d. without adverse effect on body weight. Animal Model: Balb/c mouse and SD rat[1]. Dosage: 1 mg/kg (Pharmacokinetic Analysis). Administration: IV dose: 1 mg/kg (20% Captisol with pH adjusted to 3.5 using methanesulfonic acid). Result: Exhibited CL ((L/h)/kg) values of 0.16 and 0.73, Vss (L/kg) values of 0.31 and 0.62, t1/2 (h) values of 1.3 and 1.0 in mouse and rat, respectively.

[1]. Longbin Liu, et al. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458). J Med Chem. 2008 Jul 10;51(13):3688-91.