2. Academic Validation
  3. Optimization of Aminoindazole derivatives as highly selective covalent inhibitors for wild-type and mutant FGFR4

Optimization of Aminoindazole derivatives as highly selective covalent inhibitors for wild-type and mutant FGFR4

  • Bioorg Chem. 2025 Jun 15:160:108469. doi: 10.1016/j.bioorg.2025.108469.
Jing Guo 1,  Xiaojuan Chen 2,  Xiaofei Li 1,  Xuan Wang 3,  Min Shao 1,  Xiaojuan Song 1,  Lin Zhang 2,  Shengjie Huang 1,  Adam V Patterson 4,  Jeff B Smaill 4,  Yang Zhou 1,  Xiangrong Yu 5,  Yongheng Chen 6,  Xiaoyun Lu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 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 Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 4 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 92019, New Zealand.
  • 5 Department of Radiology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai 519000, China. Electronic address: yxr00125040@126.com.
  • 6 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. Electronic address: yonghenc@163.com.
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: luxy2016@jnu.edu.cn.
PMID: 40252369 DOI: 10.1016/j.bioorg.2025.108469
Abstract

The Fibroblast Growth Factor receptor 4 (FGFR4) has emerged as a potential oncogenic driver in hepatocellular carcinoma (HCC), primarily due to aberrations in the FGFR4-FGF19 signaling axis. Although the FGFR4-selective inhibitors have been reported, none have received approval. Further, the clinical acquired resistance caused by FGFR4 mutations has become an unmet clinical need for Cancer therapy. In this study, we designed and synthesized a series of 3-amido-1H-indazole-based FGFR4 irreversible inhibitors, targeting both wild-type FGFR4 and the gatekeeper and molecular brake mutants. The representative compound, 48c, exhibited potent inhibitory activity against FGFR4WT kinase (IC50 = 2.9 nM) and picomolar activity against FGFR4WT, FGFR4V550L, and FGFR4V550M-driven Ba/F3 cell lines (IC50 < 0.1, 0.3, and 0.3 nM, respectively). 48c exhibited high selectivity across a panel of 66 kinases harboring a cysteine at the hinge region, highlighting its potential as a promising therapeutic candidate for overcoming resistance in FGFR4-associated tumors.

Keywords

Clinical resistance mutations; Covalent binding; FGFR4; Hepatocellular carcinoma.

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