OK-1035, A SELECTIVE INHIBITOR OF DNA-DEPENDENT PROTEIN-KINASE

Screening for inhibitors of DNA-dependent protein kinase (DNA-PK) reve aled -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 acti vity at 8 mu M, a concentration more than 50 times lower than those re quired against seven other protein kinases tested. OK-1035 inhibited t he phosphorylation by DNA-PK of consensus peptide as well as that of r ecombinant human wild type-p53. Kinetic studies indicated that OK-1035 inhibited DNA-PK activity in an ATP-competitive manner. (C) 1995 Acad emic Press, Inc.