Discovery of indirubin derivatives as new class of DRAK2 inhibitors from high throughput screening

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2719-23. doi: 10.1016/j.bmcl.2016.03.111. Epub 2016 Apr 1.

Abstract

DRAK2 is a serine/threonine kinase belonging to the death-associated protein kinase (DAPK) family and has emerged as a promising drug target for the treatment of autoimmune diseases and cancers. To identify small molecule inhibitors for DRAK2, we performed a high throughput screening campaign using in-house chemical library and identified indirubin-3'-monoximes as novel class of DRAK2 inhibitors. Among the compounds tested, compound 16 exhibited the most potent inhibitory activity against DRAK2 (IC50=0.003μM). We also propose that compound 16 may bind to the ATP-binding site of the enzyme based on enzyme kinetics and molecular docking studies.

Keywords: DRAK1; DRAK2; Indirubin; Inhibitor; Kinase.

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • High-Throughput Screening Assays*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology
  • 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

  • Apoptosis Regulatory Proteins
  • Indoles
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • STK17B protein, human
  • indirubin