2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4

Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4

  • J Med Chem. 2022 Mar 24;65(6):5113-5133. doi: 10.1021/acs.jmedchem.2c00096.
Min Shao 1,  Xiaojuan Chen 2,  Fang Yang 1,  Xiaojuan Song 1,  Yang Zhou 1,  Qianmeng Lin 2,  Ying Fu 2,  Raquel Ortega 3,  Xiaojing Lin 3,  Zhengchao Tu 1,  Adam V Patterson 3 4,  Jeff B Smaill 3 4,  Yongheng Chen 2,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 3 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland 92019, New Zealand.
  • 4 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag, Auckland 92019, New Zealand.
PMID: 35271262 DOI: 10.1021/acs.jmedchem.2c00096
Abstract

Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (7v) exhibited excellent potency against FGFR4, FGFR4V550L, and FGFR4V550M with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound 7v demonstrated modest in vivo antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145836
    FGFR4抑制剂
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