LAUSR

DNA-PK, the DNA-dependent protein kinase, is a validated target for cancer therapeutics that drives the DNA damage response and plays a critical role in the nonhomologous end joining (NHEJ) DNA repair pathway. Inhibition of DNA-PK activity can elicit anticancer activity and also sensitize cancer cells to DNA damaging therapy. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs is the mechanism of clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat various cancers. Modulating the pathway responsible for repairing these breaks has been shown to have a profound impact on the efficacy of IR or chemotherapy in the clinic. We have taken a completely unique and novel approach to inhibiting DNA-PK that is based on extensive knowledge regarding DNA-PK kinase activation and affords considerable advantages to current approaches in DNA-PK inhibition. DNA-PK activation and NHEJ pathway engagement requires binding of the Ku70/80 heterodimer to DNA ends and we are targeting this protein-DNA interaction. We have discovered and developed a series of highly potent and selective DNA-PK inhibitors that act via blocking the binding of Ku70/80 to DNA ends. The lead compound from this series of molecules inhibits DNA-PK catalytic activity at nanomolar concentrations, has single-agent anticancer activity in cancer cell lines, and potentiates cellular sensitivity to IR treatment and DSB-producing chemotherapeutic agents. These data demonstrate the utility of inhibiting DNA-PK via targeting the Ku-DNA interaction. Citation Format: John J. Turchi, Navnath Gavande, Pamela VanderVere-Carozza, Tyler Vernon, Katherine Pawelczak. Targeting DNA-PK via small molecule inhibitors of the Ku-DNA interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-119. doi:10.1158/1538-7445.AM2017-LB-119