Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKε kinases

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018. Epub 2012 Jan 14.

Abstract

The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.

MeSH terms

  • Aurora Kinase B
  • Aurora Kinases
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Design
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Models, Molecular
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Benzimidazoles
  • Protein Kinase Inhibitors
  • benzimidazole
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • Cyclin-Dependent Kinase 2