Discovery of novel pyrimidine-based KRAS-G12C inhibitors with potent anti-NSCLC activity via virtual screening and structure optimization.

KRAS-G12C is a validated therapeutic target for KRAS-mutant cancers. However, current KRAS-G12C inhibitors face limitations due to structural homogeneity and the emergence of drug resistance. To address this, we employed virtual screening to identify novel pyrimidine-based KRAS-G12C inhibitors, followed by rational structural optimization. Among the optimized compounds, KD36 significantly inhibited the proliferation of KRAS-G12C mutant NSCLC cell lines (NCI-H23 and NCI-H358) in a dose-dependent manner. Mechanistically, KD36 suppressed the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly, KD36 induced intrinsic (mitochondrial) apoptosis in NCI-H23 cells. Critically, in an NCI-H358 xenograft mouse model, KD36 (at 30 mg/kg) exhibited significant tumor growth inhibition with 54.6 % tumor growth inhibition (TGI), without apparent systemic toxicity. These findings establish KD36 as a promising, structurally novel pyrimidine-based KRAS-G12C inhibitor lead compound with potent anti-tumor efficacy against KRAS-G12C mutant NSCLC, demonstrating the success of our virtual screening and optimization strategy in overcoming scaffold limitations.