Structure-based design and synthesis of novel highly potent and selective KRASG12C inhibitors

The KRAS^G12C mutation is a prevalent oncogenic driver in solid tumors including non-small cell lung Cancer (NSCLC) and colorectal adenocarcinoma(CRC). While covalent KRAS^G12C inhibitors have demonstrated promising clinical outcomes, acquired secondary resistance mutations such as R68S present ongoing challenges. To expand the scope of targeted intervention, we developed a novel inhibitor series through rational core scaffold engineering by incorporating a 6,8-difluoroquinazoline core to replace traditional bicyclic systems. This design strategy yielded compounds 19 and 20, which displayed sub-nanomolar cellular potency against KRAS^G12C-driven cell proliferation (NCI-H358, IC₅₀ = 0.5 nM for both) and crucially retained potent activity against the clinically relevant KRAS G12C-R68S resistance variant (Ba/F3, IC₅₀ = 29.8 nM and 5.4 nM, respectively). Pharmacokinetic optimization achieved high oral bioavailability (F = 60.7 % for 19, F = 40.8 % for 20) with sustained tumor exposure, enabling near-complete tumor regression (TGI = 103 %) in SW837 rectal xenografts at 30 mg/kg QD without observable toxicity. These findings advance core scaffold engineering as a strategy to address resistance mechanisms while maintaining favorable pharmacological profiles. The convergence of robust cellular activity, resistance mutation coverage, and favorable drug disposition establishes 19 and 20 as advanced leads worthy of translational development for KRAS^G12C-driven cancers.

Anticancer; Colorectal adenocarcinoma; Covalent inhibitors; KRAS(G12C); Non-small cell lung cancer.