Development of novel Ku targeted kinase inhibitors

Title Development of novel Ku targeted kinase inhibitors Abstract 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 non homologous end joining NHEJ DNA repair pathway 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 cancer 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 our extensive knowledge about how the kinase is activated and affords considerable advantages to current approaches in DNA PK inhibition In the NHEJ pathway the prerequisite event for all subsequent steps is the binding of the Ku heterodimer to DNA ends and the Ku heterodimer is the key DNA binding component of the catalytic subunit of DNA PK As DNA PKcs requires Ku to first bind the DNA terminus of the DSB which then recruits and activates the kinase we have targeted this Ku DNA interaction as a novel mechanism to inhibit DNA PK We have discovered and developed a series of highly potent and selective DNA PK inhibitors that act via disrupting the binding of Ku to DNA The lead compound from this series of molecules inhibits DNA PK catalytic activity at sub micromolar concentrations has single agent anti cancer activity in cancer cell lines and potentiates cellular sensitivity to IR treatment We propose two specific aims that expand upon our identified DNA PK inhibitors and advance the development of these molecules for use as anti cancer therapeutics and to increase the efficacy of radiation and chemotherapy Health Relevance The research described in this application has direct relevance to human health in that we are proposing the development of novel agents to be used with ionizing radiation in the treatment of human cancer