2. Academic Validation
  3. Discovery of BW710 as a potent, selective and orally bioavailable fibroblast growth factor receptor 2 (FGFR2) inhibitor

Discovery of BW710 as a potent, selective and orally bioavailable fibroblast growth factor receptor 2 (FGFR2) inhibitor

  • Eur J Med Chem. 2025 Apr 5:287:117339. doi: 10.1016/j.ejmech.2025.117339.
Bowen Yang 1,  Qiuju Xun 2,  Yuan Tian 3,  Huiqiong Li 1,  Pinglian Wu 1,  Yang Zhou 4,  Shaohua Chang 5,  Zhen Wang 6,  Ke Ding 7,  Dawei Ma 8
Affiliations

Affiliations

  • 1 Chang-Kung Chuang Institute, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 2 Shanghai Key Laboratory for Cancer System Regulation and Clinical Translation, Jiading District Central Hospital, Renji Hospital Jiading Branch, Shanghai, 201800, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China.
  • 5 KinoTeck Therapeutics Co., Ltd, 35 Sicheng Road, Tianhe District, Guangzhou, 510663, China.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: wangz@sioc.ac.cn.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: dingk@sioc.ac.cn.
  • 8 Chang-Kung Chuang Institute, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: madw@sioc.ac.cn.
PMID: 39908791 DOI: 10.1016/j.ejmech.2025.117339
Abstract

While Fibroblast Growth Factor receptor 2 (FGFR2) emerges as an appealing Cancer therapeutic target, so far there is no selective FGFR2 Inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC50 value of 2.8 nM, and was much less active against BaF3-FGFR1 and parental BaF3 cells with IC50 values of >1000 nM. Kinase selectivity profiling revealed that BW710 completely abolished FGFR2 enzymatic activity and was selective against Other 75 tyrosine kinases including FGFR1, FGFR3, and FGFR4 at 1 μM. The covalent binding mode between BW710 and FGFR2 was confirmed by MS spectrometry. Further evaluation showed that BW710 potently suppressed the FGFR2 signaling and selectively inhibited FGFR2-driven Cancer cell proliferation. Additionally, BW710 also displayed reasonable pharmacokinetic properties with an oral bioavailability of 29 % in mice. Taken together, this study provides a potent, selective and orally bioavailable FGFR2 Inhibitor for further development of FGFR2-targeted therapeutic agents.

Keywords

Antiproliferation; FGFR2; Irreversible inhibitor; Orally bioavailable; Selectivity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170934
    FGFR2抑制剂
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