Discovery of Novel 2,4,5-Trisubstituted Pyrimidine Derivatives as Potent and Selective FGFR Inhibitors against Gatekeeper Mutants for the Treatment of NSCLC

  • J Med Chem. 2025 Mar 13;68(5):5907-5925. doi: 10.1021/acs.jmedchem.5c00124.
Jianxia Zhang  1 ,  Yi Wang  1 ,  Mengying Wang  1 ,  Peipei Wang  1 ,  Hao Yan  1 ,  Dalong Wang  1 ,  Jiahao Zheng  1 ,  Bin Li  1 ,  Chaoyue Chen  1 ,  Di Cao  1 ,  Xiaohui Zheng  1 ,  Xiaokun Li  1 ,  Kun Wang  1 ,  Zhiguo Liu  1
Affiliations
  • 1. State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People's Republic of China.
PMID: 40032550 DOI: 10.1021/acs.jmedchem.5c00124
Abstract

Fibroblast Growth Factor receptors (FGFRs) play a critical role in the regulation of Cancer cell proliferation, differentiation, and migration. However, the development of acquired resistance to FGFR inhibitors remains a major challenge in treating non-small cell lung Cancer (NSCLC), particularly due to mutations at the gatekeeper residue. In this study, we report the discovery of a series of irreversible FGFR inhibitors targeting gatekeeper mutations in FGFR1-3, utilizing a 2,4,5-trisubstituted pyrimidine scaffold. Through rational design, structure-activity relationship optimization, and pharmacokinetic evaluation, compound ng 12l emerged as a promising candidate. It demonstrated potent inhibition of FGFR1-3 gatekeeper mutations in vitro along with favorable pharmacokinetic properties. The efficacy of 12l in targeting FGFR1 gatekeeper mutations was confirmed in assays using L6-FGFR1V561M/F cells. Furthermore, in xenograft models using both H1581 and L6-FGFR1V561M cells, 12l exhibited robust anti-tumor activity with minimal toxicity. These findings position 12l as a promising therapeutic agent for overcoming gatekeeper-mediated resistance in NSCLC.

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