Benzisothiazole derivatives as KRAS G12C inhibitors for potential treatment of non-small cell lung cancer.

KRAS G12C mutation is a key driver of multiple solid tumors, and has recently become a crucial target for therapy via small molecules that covalently bind to the mutated cysteine. Herein, a series of benzisothiazole derivatives is presented as KRAS G12C inhibitors utilizing a scaffold-hopping strategy. Among them, S32 exhibited remarkable antiproliferative efficacy, specifically in the NCI-H23 cell line (IC50 = 0.55 ± 0.05 μM). Docking studies of S32 revealed that the oxygen atom of the trifluoroethoxy group at the C-7 position of benzisothiazole formed a hydrogen bond with His95 and extended into a solvent-exposed region. Additionally, S32 obviously inhibited nucleotide exchange efficiency, stabilizing KRAS in the GDP-bound state and inhibited the downstream ERK/AKT signaling pathways of KRAS in NCI-H23 and NCI-H358 cells, while inducing apoptosis by upregulating BAX and downregulating BCL-2 apoptotic proteins. Furthermore, S32 achieved a tumor growth inhibition (TGI) of 90.8% at a dose of 30 mg/kg. These results confirmed that S32, with a benzisothiazole scaffold, was an effective KRAS G12C inhibitor, potentially promoting cancer therapy development.