Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase

Biol Pharm Bull. 2009 Feb;32(2):297-300. doi: 10.1248/bpb.32.297.


Phosphatidylinositol 3-kinase (PI3K) has been implicated in a variety of diseases including cancer. A number of PI3K inhibitors have recently been developed for use in cancer therapy. ZSTK474 is a highly promising antitumor agent targeting PI3K. We previously reported that ZSTK474 showed potent inhibition against four class I PI3K isoforms but not against 140 protein kinases. However, whether ZSTK474 inhibits DNA-dependent protein kinase (DNA-PK), which is structurally similar to PI3K, remains unknown. To investigate the inhibition of DNA-PK, we developed a new DNA-PK assay method using Kinase-Glo. The inhibition activity of ZSTK474 against DNA-PK was determined, and shown to be far weaker compared with that observed against PI3K. The inhibition selectivity of ZSTK474 for PI3K over DNA-PK was significantly higher than other PI3K inhibitors, namely NVP-BEZ235, PI-103 and LY294002. These results indicated that ZSTK474 was the most specific agent among these PI3K inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromones / pharmacology
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • Enzyme Inhibitors / pharmacology*
  • Furans / pharmacology
  • Imidazoles / pharmacology
  • Morpholines / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Triazines / pharmacology*


  • Chromones
  • Enzyme Inhibitors
  • Furans
  • Imidazoles
  • Morpholines
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Quinolines
  • Triazines
  • ZSTK474
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • DNA-Activated Protein Kinase
  • dactolisib