Discovery of 6-aryl-azabenzimidazoles that inhibit the TBK1/IKK-ε kinases

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1138-43. doi: 10.1016/j.bmcl.2013.12.123. Epub 2014 Jan 13.

Abstract

The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.

Keywords: Azabenzimidazole; IKK-ε; Kinase inhibitor; TBK1.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase