Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2448-52. doi: 10.1016/j.bmcl.2014.04.023. Epub 2014 Apr 16.

Abstract

There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.

Keywords: ITK; Indazole; SBDD; X-ray crystallography; π-stacking.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Jurkat Cells
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase