2. Academic Validation
  3. Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors

Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors

  • J Med Chem. 2018 Oct 25;61(20):9085-9104. doi: 10.1021/acs.jmedchem.7b01843.
Yuming Wang 1 2,  Lijun Li 3 2,  Jun Fan 1 2,  Yang Dai 3 2,  Alan Jiang 3 2,  Meiyu Geng 3 2,  Jing Ai 3 2,  Wenhu Duan 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry , Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , 555 Zu Chong Zhi Road , Shanghai 201203 , P. R. China.
  • 2 University of Chinese Academy of Sciences , No.19A Yuquan Road , Beijing 100049 , P. R. China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , 555 Zu Chong Zhi Road , Shanghai 201203 , P. R. China.
PMID: 29522671 DOI: 10.1021/acs.jmedchem.7b01843
Abstract

Fibroblast Growth Factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2/KDR/Flk-1 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.

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