Sotorasib CAS# 2252403-56-6 6-氟-7-(2-氟-6-羟基苯基)-1-[4-甲基-2-(1-甲基乙基)-3-吡啶基]-4-[(2S)-2-甲基-4-(1-氧代-2-丙烯-1-基)-1-哌嗪基]-吡啶并[2,3-d]嘧啶-2(1H)-酮

Sotorasib (AMG 510) is a first-in-class, selective, covalent inhibitor of KRAS^G12C^. In preclinical biochemical assays, it irreversibly bound the mutant cysteine residue in KRAS^G12C^, locking it in the inactive GDP-bound state with an IC50 of ~2.3 nM. In KRAS^G12C^-mutant cancer cell lines, sotorasib inhibited downstream ERK phosphorylation, induced apoptosis, and suppressed proliferation (IC50 values 30–100 nM). In xenograft mouse models of KRAS^G12C^-driven tumors, daily oral dosing caused marked tumor regression and prolonged survival. Pharmacokinetic studies demonstrated favorable oral bioavailability, sustained target occupancy, and dose-proportional plasma exposure. These results validated direct KRAS^G12C^ inhibition as an effective anticancer strategy.