2. Academic Validation
  3. Design of fibroblast growth factor receptor (FGFR) inhibitors containing a 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one motif

Design of fibroblast growth factor receptor (FGFR) inhibitors containing a 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one motif

  • Eur J Med Chem. 2026 Sep 15:314:118912. doi: 10.1016/j.ejmech.2026.118912.
Yuanli Yang 1,  Ziwei Wang 1,  Yu Zhang 1,  Juan Xu 2,  Yuanyuan Li 2,  Huaxiang Fang 3,  Huan He 4,  Silong Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China.
  • 2 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 561113, PR China.
  • 3 Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
  • 4 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China. Electronic address: [email protected].
  • 5 Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China. Electronic address: [email protected].
PMID: 42134161 DOI: 10.1016/j.ejmech.2026.118912
Abstract

The Fibroblast Growth Factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and various Other physiological processes. In this study, we have designed and synthesized a series of FGFR inhibitors featuring the 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one scaffold as a core structural motif. Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR Inhibitor. In preclinical evaluations, 1a exhibited remarkable pharmacokinetic properties (oral bioavailability = 66.9%). In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR Inhibitor for Cancer treatment, supporting its further development in clinical settings.

Keywords

FGFR; Hepatocellular carcinoma; Ligand-based design.

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