Discovery of ASP2453, a potent and orally bioavailable covalent inhibitor of KRAS G12C for the treatment of solid tumors

KRAS G12C has recognized as a promising therapeutic target for the treatment of solid tumors. Our previous work identified ASP6918 ( 1 ) as a KRAS G12C inhibitor that demonstrated a dose-dependent tumor regression in an NCI-H1373 (KRAS G12C-mutated cell line) xenograft mouse model following oral administration. However, ASP6918 exhibited unfavorable pharmacokinetics with high systemic clearance in monkeys. In this report, we carried out further optimization of ASP6918 to improve its the pharmacokinetic profile. Optimization of substituents on the quinazoline scaffold and the N-alkyl substituent on the piperidine moiety led to the discovery of ASP2453 ( 27 ), which showed improved total clearance in monkeys compared to ASP6918. ASP2453 also exhibited more potent in vitro activity and ASP2453 induced dose-dependent tumor regression at lower oral administration in an NCI-H1373 xenograft mouse model, without significant body weight loss. These findings provide valuable insights into the structure-activity relationship (SAR) of KRAS G12C inhibitors and their pharmacokinetic optimization. • Discovery of a potent and orally bioavailable covalent inhibitor of KRAS G12C was described. • ASP2453 ( 27 ) showed potent cellular inhibition of ERK phosphorylation and cell growth inhibition against the KRAS G12C mutation-positive NSCLC cell line NCI-H1373. • ASP2453 exhibited improved total clearance in monkeys compared to ASP6918. • In an NCI-H1373 xenograft mouse model, repeated oral administration of ASP2453 at 10 and 30 mg/kg resulted in tumor regression rates of 47 % and 86 %, respectively, without significant body weight loss.