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DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection and repair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents, including chemotherapy, radiation or PARP inhibitors such as olaparib (Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells) and >100x selective against 396 other kinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics in preclinical species. In murine xenograft models, PD was assessed using pRPA (S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor, with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019. Citation Format: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies. Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT01-02.