2. Academic Validation
  3. Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants

Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants

  • Eur J Med Chem. 2023 Oct 5;258:115628. doi: 10.1016/j.ejmech.2023.115628.
Yingyue Yang 1,  Xiaojie He 1,  Zulong Li 1,  Kai Ran 2,  Ningyu Wang 3,  Lifeng Zhao 4,  Zhihao Liu 1,  Jun Zeng 1,  Bo Chang 5,  Qiang Feng 5,  Qiangsheng Zhang 6,  Luoting Yu 7
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
  • 3 School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan, 611756, China.
  • 4 Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
  • 5 College of Chemistry and Life Science, Chengdu Normal University, Chengdu, 611130, PR China.
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 7 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37437349 DOI: 10.1016/j.ejmech.2023.115628
Abstract

Fibroblast Growth Factor receptor 4 (FGFR4) has been proved to be an effective target for Cancer therapy. Aberration in FGF19/FGFR4 signaling is oncogenic driving force in human hepatocellular carcinoma (HCC). FGFR4 gatekeeper mutations induced acquired resistance remains an unmet clinical challenge for HCC treatment. In this study, a series of 1H-indazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. These new derivatives showed significant FGFR4 inhibitory and antitumor activities, among which compound 27i was demonstrated to be the most potent compound (FGFR4 IC50 = 2.4 nM). Remarkably, compound 27i exhibited no activity against a panel of 381 kinases at 1 μM. Additionally, compound 27i displayed nanomolar IC50s against huh7 (IC50 = 21 nM) and two mutant cell lines, BaF3/ETV6-FGFR4-V550L and BaF3/ETV6-FGFR4-N535K (IC50 = 2.5/171 nM). Meanwhile, compound 27i exhibited potent antitumor potency (TGI: 83.0%, 40 mg/kg, BID) in Huh7 xenograft mouse models with no obvious toxicity observed. Overall, compound 27i was identified as a promising preclinical candidate for overcoming FGFR4 gatekeeper mutations for HCC treatment.

Keywords

Anti-cancer agents; FGFR4 inhibitors; Gatekeeper mutation; HCC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155046
    FGFR4 Inhibitor