Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects

J Med Chem. 2019 Mar 28;62(6):2905-2915. doi: 10.1021/acs.jmedchem.8b01531. Epub 2018 Nov 16.


Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / pathology
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology
  • Molecular Dynamics Simulation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 4 / chemistry
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism
  • Signal Transduction / drug effects


  • Protein Kinase Inhibitors
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4