2. Academic Validation
  3. Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4

Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4

  • Eur J Med Chem. 2024 Feb 28:268:116281. doi: 10.1016/j.ejmech.2024.116281.
Xiaojuan Chen 1,  Huiliang Li 2,  Qianmeng Lin 1,  Shuyan Dai 3,  Lingzhi Qu 1,  Ming Guo 1,  Lin Zhang 1,  Jiaxuan Liao 4,  Hudie Wei 1,  Guangyu Xu 5,  Longying Jiang 6,  Yongheng Chen 7
Affiliations

Affiliations

  • 1 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; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 2 Key Laboratory of Chemical Biology and Traditional Chinese Medicine, Ministry of Educational of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, Hunan, China.
  • 3 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
  • 4 HD Shanghai School, Shanghai, 201613, China.
  • 5 Key Laboratory of Chemical Biology and Traditional Chinese Medicine, Ministry of Educational of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, Hunan, China. Electronic address: [email protected].
  • 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; Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
  • 7 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; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
PMID: 38432058 DOI: 10.1016/j.ejmech.2024.116281
Abstract

Aberrant signaling via Fibroblast Growth Factor 19 (FGF19)/Fibroblast Growth Factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for Anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast Cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 Inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future Anticancer drug discovery.

Keywords

Antitumor activity; Breast cancer; Covalent inhibitors; FGFR4; FGFR4 cysteine mutants.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161326
    FGFR4 Inhibitor