NU5455 (NU-5455) is a potent, highly selective, oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity with IC50 of 8.2 nM.
NU5455 displays selectivity versus Vps34 (8.7-fold), PI3Kδ (33.7-fold), ATM/ATR (both >1200-fold), 228-fold selectivity margin for DNA-PKcs kinase activity versus that of PI3Kα.
NU5455 inhibited radiation-induced activation of DNA-PK with an IC50 of 168 nM, but did not inhibit IGF-stimulated activation of AKT in MCF7 cells even at 10 uM.
NU5455 inhibited the repair of DNA-DSBs induced by treatment with enzyme AfeI or ScaI restriction endonucleases within a 24-hour period in HEK293T cells, significantly increased the number of colocalized γH2AX and 53BP1 foci.
NU5455 is a highly selective inhibitor of DNA-PKcs that is active in cells and that can perturb DNA-DSB repair by NHEJ.
NU5455 preferentially augmented radiotherapy in subcutaneous Calu-6 and A549 lung tumor xenografts, increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, NU5455 enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect.