2. Academic Validation
  3. Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors

Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors

  • Eur J Med Chem. 2024 May 5:271:116415. doi: 10.1016/j.ejmech.2024.116415.
Yuanjiang Wang 1,  Yanchang Pan 2,  Zhaodan Lv 2,  Shaohua Gou 3
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, PR China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, PR China.
  • 2 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, PR China.
  • 3 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, PR China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, 211189, PR China. Electronic address: sgou@seu.edu.cn.
PMID: 38643670 DOI: 10.1016/j.ejmech.2024.116415
Abstract

Fibroblast Growth Factor receptor (FGFR) is an attractive target for Cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on Enzyme activity inhibition and anti-proliferative activity against the tested Cancer cell lines. Significantly, III-30 could inhibit the Enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote Cancer cell Apoptosis and inhibit Cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.

Keywords

Anti-tumor activity; FGFR; FGFR inhibitor; Irreversible covalent inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163527
    FGFR抑制剂
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