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
  • 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.
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