2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 2-Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors

Design, Synthesis, and Biological Evaluation of 2-Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors

  • J Med Chem. 2022 Feb 24;65(4):3249-3265. doi: 10.1021/acs.jmedchem.1c01816.
Zhen Zhang 1,  Jie Li 1,  Hao Chen 1,  Jing Huang 1,  Xiaojuan Song,  Zheng-Chao Tu 1 2,  Zhang Zhang 1,  Lijie Peng 1,  Yang Zhou 1,  Ke Ding 1 3 4
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, College of Pharmacy, Jinan University, # 855 Xingye Avenue, Guangzhou 510632, China.
  • 2 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, # 160 Kaiyuan Avenue, Guangzhou 510530, China.
  • 3 The First Affiliated Hospital, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, # 345 Lingling Road, Shanghai 200032, China.
PMID: 35119278 DOI: 10.1021/acs.jmedchem.1c01816
Abstract

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound 9ka exhibited an IC50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome selectivity. Compound 9ka also exhibited good oral pharmacokinetic properties with an AUC(0-t) value of 38 950.06 h·ng/mL, a T1/2 value of 3.06 h, and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon 30 mg/kg oral administration. Compound 9ka may serve as a promising lead compound for further Anticancer drug development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143881
    FGFR4抑制剂
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