Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 32, Issue 2, Pages 297-300Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.32.297
Keywords
phosphatidylinositol 3-kinase; DNA-dependent protein kinase; ZSTK474; inhibitor; specificity
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Funding
- National Institute of Biomedical Innovation, Japan [05-13]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20015048]
- Japan Society for the Promotion of Science [17390032]
- Grants-in-Aid for Scientific Research [17390032, 20015048] Funding Source: KAKEN
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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. Ne 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.
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