Design, synthesis and pharmacological evaluation of bicyclic and tetracyclic pyridopyrimidinone analogues as new KRASG12C inhibitors

KRAS is the most commonly altered oncogene of RAS family, especially G12C mutant (KRASG12C), which has been a promising drug target for many cancers. On basis bicyclic pyridopyrimidinone framework first-in-class clinical KRASG12C inhibitor AMG510, scaffold hopping strategy was conducted including F–OH cyclization approach and pyridinyl N-atom working leading to new tetracyclic analogues. Compound 26a identified possessing binding potency 1.87 ?M against cell growth inhibition 0.79 in MIA PaCa-2 pancreatic cancer cells. Treatment with NCI–H358 cells resulted down-regulation KRAS-GTP levels reduction phosphorylation downstream ERK AKT dose-dependently. Molecular docking suggested that fluorophenol moiety occupies hydrophobic pocket region thus forming hydrogen bonding Arg68. These results will be useful guide further structural modification.