tcsc3282 AMG 232

AMG 232 is an extremely potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC₅₀ of 0.6 nM, and binds to MDM2 with a K_d of 0.045 nM.

IC50 & Target: IC50: 0.6 nM (p53-MDM2 interaction)^[1]


Kd: 0.045 nM (MDM2)^[1]

In Vitro: AMG 232 (10 μM) induces p53 signaling and inhibits tumor cell proliferation in three p53 wild-type tumor cell lines (SJSA-1, HCT116, and ACHN)^[1]. AMG 232 significantly inhibits the human MDM2-p53 interaction in the biochemical HTRF-based assay (IC₅₀=0.6 nM). AMG 232 potently inhibits proliferation of non-MDM2-amplified HCT116 colorectal cells in the BrdU assay (IC₅₀=10 nM)^[3].

In Vivo: AMG 232 (10, 25, 75 mg/kg, p.o.) activates p53 pathway activity in vivo. AMG 232 (100 mg/kg, p.o.) results in 86% TGI compared with control, and the ED₅₀ is 31 mg/kg in the HCT116 colorectal cancer model (KRAS mutant), and results in 97% TGI, with an ED₅₀ of 18 mg/kg in an A375sq2 BRAF-mutant melanoma model^[1]. AMG 232 exhibits low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%)^[2]. AMG 232 displays robust tumor growth inhibition compared to the vehicle, with an ED₅₀ of 9.1 mg/kg q.d. AMG 232 causes a dose-dependent tumor growth inhibition with an ED₅₀ of 16 mg/kg^[3].