Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries

Bioorg Med Chem Lett. 2004 Dec 20;14(24):6083-7. doi: 10.1016/j.bmcl.2004.09.060.

Abstract

A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a highly potent and selective DNA-PK inhibitor (IC50=14 nM), exhibiting ATP-competitive inhibition kinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromones / chemical synthesis
  • Chromones / chemistry*
  • Chromones / pharmacology*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
  • Chromones
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Morpholines
  • DNA-Activated Protein Kinase
  • Protein Serine-Threonine Kinases