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

KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRAS(G12C)), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS(G12C) inhibitor AMG510, a scaffold hopping strategy was conducted including a F-OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 mu M against KRAS(G12C) and cell growth inhibition of 0.79 mu M in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI-H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

A new compound 26a was designed based on the KRAS(G12C) inhibitor AMG510, showing significant binding affinity and cell growth inhibition against pancreatic cancer cells, suggesting potential therapeutic effects through regulation of KRAS-GTP levels and downstream ERK and AKT phosphorylation.