title: Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase.
abstract: 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.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Yaguchi
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D002867:Chromones / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014227:Triazines / Q000494:pharmacology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D005663:Furans; D007093:Imidazoles; D009025:Morpholines; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D014227:Triazines; C510150:ZSTK474; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051747:DNA-Activated Protein Kinase; C531198:dactolisib