Discovering novel 7-azaindole-based series as potent AXL kinase inhibitors

Bioorg Med Chem Lett. 2017 Feb 15;27(4):862-866. doi: 10.1016/j.bmcl.2017.01.015. Epub 2017 Jan 9.

Abstract

AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL.

Keywords: 7-Azaindole; AXL; Kinase inhibitor; Medicinal chemistry; Modeling study; Receptor tyrosine kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Axl Receptor Tyrosine Kinase
  • Binding Sites
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Humans
  • Indoles / chemistry*
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism

Substances

  • 7-azaindole dimer
  • Indoles
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Adenosine Triphosphate
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human