Design, synthesis and evaluation of quinazoline-6-carbonitrile derivatives as novel covalent KRASG12C inhibitors for the treatment of NSCLC.

KRASG12C mutation occurs in approximately 14% of lung adenocarcinoma cases and has emerged as an important therapeutic target in precision oncology. In this study, a series of novel quinazoline-6-carbonitrile derivatives were developed as KRASG12C covalent inhibitors. Among them, the representative compound 8t displayed significant inhibitory activity against KRASG12C in biochemical assay and KRASG12C-mutant non-small cell lung cancer H358 cells with IC50 values of 3.13 and 1.8 nM, respectively. It also effectively blocked ERK and AKT phosphorylation with IC50 value of 4.67 and 23.74 nM, respectively. LCMS analysis confirmed that compound 8t binds to KRASG12C rapidly and covalently. In addition, 8t demonstrated moderate metabolic stability in human liver microsomes and moderate oral bioavailability in mice. Furthermore, compound 8t showed partial antitumor efficacy in H358 xenograft models following once-daily dosing at 30 mg/kg, without causing significant body weight loss. These findings indicated that 8t could serve as a promising lead compound for the treatment of KRASG12C-mutant NSCLC.