AMG458 是一种口服有活力的c-Met选择性抑制剂，其对人和小鼠的Ki分别为 1.2 nM 和 2.0 nM。

AMG 458 is a potent c-Met inhibitor with Ki of 1.2 nM, ~350-fold selectivity for c-Met than VEGFR2 in cells.

AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM. [1] AMG 458 is observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. AMG 458 is believed to react with thiol groups in proteins, producing a methoxy quinoline thioether conjugate. [2] A recent study shows that the constitutive phosphorylation of c-Met in H441 is abrogated by AMG 458. The basal and HGF-induced phosphorylation of c-Met in A549 is attenuated by AMG 458. The combination of radiation therapy and AMG 458 treatment is found to synergistically increase apoptosis in the H441 cell line by reduction of p-Akt and p-Erk levels, but not in A549. [3]

AMG 458 is metabolically stable in the liver microsomes of mouse, rat, dog, monkey, and human with low intrinsic clearances (Clint:<5, 62, 8, 8, 18 (μL/min)/mg, respectively). When administered orally, AMG 458 achieves remarkably high bioavailability in all species tested. Oral dosing of AMG 458 inhibits HGF-mediated c-Met phosphorylation with an approximate ED90 of 30 mg/kg and an associated plasma exposure of approximately 15 μM at 6 hours. AMG 458 significantly inhibits tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models at 30 and 100 mg/kg q.d. and 30 mg/kg b.i.d.with no adverse effect on body weight. [1] High concentrations of AMG 458 in some organs may produce toxicity via oxidative stress. [2]

913376-83-7

C30H29N5O5

539.592

AMG 458

H2O:<1 mgml
DMSO:21 mg/mL (38.91 mM)
Ethanol:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years