Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

Molecules. 2018 Mar 19;23(3):698. doi: 10.3390/molecules23030698.

Abstract

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development.

Keywords: FGFR; cancer; kinase inhibitor; pyrrolo[2,3-b]pyrazine.

MeSH terms

  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Discovery*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Receptors, Fibroblast Growth Factor