Structure-activity relationship studies of Imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives to develop selective FGFR inhibitors as anticancer agents for FGF19-overexpressed hepatocellular carcinoma

Eur J Med Chem. 2025 Jan 15:282:117047. doi: 10.1016/j.ejmech.2024.117047. Epub 2024 Nov 12.

Abstract

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).

Keywords: Fibroblast growth factor receptor (FGFR); Hepatocellular carcinoma (HCC); Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor*
  • Fibroblast Growth Factors* / antagonists & inhibitors
  • Fibroblast Growth Factors* / metabolism
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / pathology
  • Male
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines* / chemical synthesis
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Receptors, Fibroblast Growth Factor* / antagonists & inhibitors
  • Receptors, Fibroblast Growth Factor* / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • Protein Kinase Inhibitors
  • FGF19 protein, human
  • Imidazoles