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
  • 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.

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