Discovery and Biological Evaluation of a Series of Pyrrolo[2,3-b]pyrazines as Novel FGFR Inhibitors

Molecules. 2017 Apr 5;22(4):583. doi: 10.3390/molecules22040583.

Abstract

Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors.

Keywords: FGFR1; hinge binder; inhibitor; kinase inhibitor; pyrazine.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Enzyme Activation
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / chemistry*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyrazines
  • Receptors, Fibroblast Growth Factor