2. Academic Validation
  3. Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor

Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor

  • Eur J Med Chem. 2024 Jun 5:272:116473. doi: 10.1016/j.ejmech.2024.116473.
Huiqiong Li 1,  Ran Ke 2,  Yang Zhou 3,  Shaohua Chang 4,  Jie Wang 3,  Chen Su 5,  Pinglian Wu 1,  Bowen Yang 1,  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 Rd., Shanghai, 200241, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China.
  • 3 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.
  • 4 Kinoteck Therapeutics CO., LTD, #6 Lane 333, Huaxia East Road, Pudong New Area, Shanghai, 202110, China.
  • 5 National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., 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 Rd., Shanghai, 200032, China; 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. Electronic address: dingk@sioc.ac.cn.
  • 8 Chang-Kung Chuang Institute, School of Chemistry and Molecular Engineering, East China Normal University, #500 Dongchuan Rd., Shanghai, 200241, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China. Electronic address: madw@sioc.ac.cn.
PMID: 38718625 DOI: 10.1016/j.ejmech.2024.116473
Abstract

Fibroblast Growth Factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven Cancer cell proliferation, and induced Apoptosis of FGFR2-driven Cancer cells. Taken together, this study provides a potent and highly selective FGFR2 Inhibitor for further development of FGFR2-targeted therapeutic agents.

Keywords

Antiproliferation; Apoptosis; FGFR2; Irreversible inhibitor; Selectivity.

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