OK-1035, a Selective Inhibitor of DNA-Dependent Protein Kinase

• Published in: Biochemical and biophysical research communications 1995-10, Vol.215 (1), p.41-47
• Main Authors: Take, Y., Kumano, M., Hamano, Y., Fukatsu, H., Teraoka, H., Nishimura, S., Okuyama, A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Caseins - metabolism; Consensus Sequence; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Inhibitors - pharmacology; HeLa Cells - enzymology; Humans; Hydrazones - chemistry; Hydrazones - pharmacology; Kinetics; Molecular Sequence Data; Molecular Structure; Nuclear Proteins; Peptides - chemistry; Peptides - metabolism; Phosphorylation; Phosphoserine - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyridones - chemistry; Pyridones - pharmacology; Structure-Activity Relationship; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1995.2431

Screening for inhibitors of DNA-dependent protein kinase (DNA-PK) revealed 3-cyano-5-(4-pyridyl)-6-hydrazonomethyl-2-pyridone, designated OK-1035, to be a potent and selective inhibitor. When a synthetic peptide was used as a substrate, OK-1035 caused 50% inhibition of DNA-PK activity at 8 μM, a concentration more than 50 times lower than those required against seven other protein kinases tested. OK-1035 inhibited the phosphorylation by DNA-PK of consensus peptide as well as that of recombinant human wild type-p53. Kinetic studies indicated that OK-1035 inhibited DNA-PK activity in an ATP-competitive manner.