title: OK-1035, a selective inhibitor of DNA-dependent protein kinase.
abstract: 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 microM, 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.
authors.affiliation: Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Take
authors.forename: M
authors.initials: M
authors.lastname: Kumano
authors.forename: Y
authors.initials: Y
authors.lastname: Hamano
authors.forename: H
authors.initials: H
authors.lastname: Fukatsu
authors.forename: H
authors.initials: H
authors.lastname: Teraoka
authors.forename: S
authors.initials: S
authors.lastname: Nishimura
authors.forename: A
authors.initials: A
authors.lastname: Okuyama
mesh_terms: D000595:Amino Acid Sequence; D002364:Caseins / Q000378:metabolism; D016384:Consensus Sequence; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009687:Nuclear Proteins; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C095985:3-cyano-5-(4-pyridyl)-6-hydrazonomethyl-2-pyridone; D002364:Caseins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006835:Hydrazones; D009687:Nuclear Proteins; D010455:Peptides; D011728:Pyridones; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases