DNA-dependent protein kinase (DNA-PK) inhibitors: structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Bioorg Med Chem Lett. 2011 Feb 1;21(3):966-70. doi: 10.1016/j.bmcl.2010.12.047. Epub 2010 Dec 13.

Abstract

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC(50)=8 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Chromones / chemical synthesis
  • Chromones / chemistry*
  • Chromones / pharmacology
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • DNA-Activated Protein Kinase / metabolism
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Chromones
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • DNA-Activated Protein Kinase