Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling

Cancer Cell. 2013 Apr 15;23(4):489-501. doi: 10.1016/j.ccr.2013.02.018.

Abstract

The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.

MeSH terms

  • Allosteric Regulation / drug effects
  • Binding, Competitive
  • Cell Growth Processes / drug effects
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Conformation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Receptors, Fibroblast Growth Factor
  • Small Molecule Libraries

Associated data

  • PDB/4J23