Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors

J Med Chem. 2013 Feb 14;56(3):1160-70. doi: 10.1021/jm3016014. Epub 2013 Jan 22.

Abstract

Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Models, Molecular
  • Pyridines / chemistry
  • Pyridines / pharmacology*

Substances

  • Pyridines
  • Focal Adhesion Protein-Tyrosine Kinases

Associated data

  • PDB/4GU6
  • PDB/4GU9