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

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

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118354. doi: 10.1016/j.ejmech.2025.118354.
Jian-Tao Shi 1,  Su-Juan Hou 1,  Cheng-Long Xu 2,  Lei Cheng 1,  Feng-Ya Ge 1,  Xiu-Juan Liu 1,  Yi-Ru Wang 1,  Xi-Bo Wang 1,  Yao-Sheng Zhang 1,  Junmin Zhang 3,  Shi-Wu Chen 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Collaborative Innovation Center for Northwestern Chinese Medicine, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China.
  • 2 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
  • 3 School of Pharmacy, Collaborative Innovation Center for Northwestern Chinese Medicine, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Collaborative Innovation Center for Northwestern Chinese Medicine, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
PMID: 41252935 DOI: 10.1016/j.ejmech.2025.118354
Abstract

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.

Keywords

Apoptosis; KRAS-G12C; NSCLC; Pyrimidine; Structure-activity relationship.

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