Discovery of novel TAOK2 inhibitor scaffolds from high-throughput screening

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3923-7. doi: 10.1016/j.bmcl.2016.07.016. Epub 2016 Jul 6.

Abstract

The MAP3K (Mitogen Activated Protein Kinase Kinase Kinase) TAOK2 (Thousand-And-One Kinase 2) is an activator of p38 MAP kinase cascade that is up-regulated in response to environmental stresses. A synthetic lethal screen performed using a NSCLC (non-small cell lung cancer) cell line, and a second screen identifying potential modulators of autophagy have implicated TAOK2 as a potential cancer therapeutic target. Using a 200,000 compound high throughput screen, we identified three specific small molecule compounds that inhibit the kinase activity of TAOK2. These compounds also showed inhibition of autophagy. Based on SAR (structure-activity relationship) studies, we have predicted the modifications on the reactive groups for the three compounds.

Keywords: Autophagy; Drug discovery; High-throughput screening; Inhibitor; Kinase; MAP3K.

MeSH terms

  • Autophagy / drug effects
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / toxicity
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / toxicity
  • Structure-Activity Relationship
  • Transition Temperature
  • p38 Mitogen-Activated Protein Kinases / chemistry
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases