Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor

J Med Chem. 2020 Jan 23;63(2):601-612. doi: 10.1021/acs.jmedchem.9b01460. Epub 2020 Jan 10.

Abstract

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Discovery
  • High-Throughput Screening Assays
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • Models, Molecular
  • Phosphorylation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

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