Structural Characterization of the Interaction of the Fibroblast Growth Factor Receptor with a Small Molecule Allosteric Inhibitor

Chemistry. 2018 Jun 4;24(31):7861-7865. doi: 10.1002/chem.201801770. Epub 2018 May 3.

Abstract

The interaction of fibroblast growth factors (FGFs) with their fibroblast growth factor receptors (FGFRs) are important in the signaling network of cell growth and development. SSR128129E (SSR), a ligand of small molecular weight with potential anti-cancer properties, acts allosterically on the extracellular domains of FGFRs. Up to now, the structural basis of SSR binding to the D3 domain of FGFR remained elusive. This work reports the structural characterization of the interaction of SSR with one specific receptor, FGFR3, by NMR spectroscopy. This information provides a basis for rational drug design for allosteric FGFR inhibitors.

Keywords: FGFR; NMR Spectroscopy; SSR128129E; allostery; inhibitor.

MeSH terms

  • Allosteric Regulation
  • Antineoplastic Agents / chemistry*
  • Drug Design
  • Indolizines / chemistry*
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / chemistry
  • Structure-Activity Relationship
  • Thermodynamics
  • ortho-Aminobenzoates / chemistry*

Substances

  • Antineoplastic Agents
  • Indolizines
  • Protein Kinase Inhibitors
  • Receptors, Fibroblast Growth Factor
  • SSR128129E
  • ortho-Aminobenzoates