DNA-dependent protein kinase (DNA-PK) binds to strand breaks produced during normal cellular processes or in response to genotoxic stresses, such as ionizing radiation, targeting substrates that facilitate DNA repair. NU 7026 is a cell-permeable, potent, specific, and ATP-competitive inhibitor of DNA-PK (IC50 = 230 nM). It poorly inhibits phosphioinositide 3 kinase (IC50 = 13 μM) and is inactive against ataxia telangiectasia mutated kinase, ATR, and poly (ADP-ribose) polymerase. NU 7026 impairs cellular DNA double strand break repair and decreases survival in cells exposed to ionizing radiation. It also potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. For example, it potentiates the growth inhibitory effects of mitoxantrone in K562 cells more than 10-fold.
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