Tumour hypoxia presents a barrier to conventional chemotherapy and radiation therapy. To combat hypoxic cells a number of hypoxia modifying treatments are currently in development. In this study we assessed the potential for inhibiting DNA double strand break repair in hypoxic cells by targeting DNA-dependent protein kinase (DNA-PK) and we report the synthesis and in vitro efficacy of BCCA621C (1), a hypoxia activated inhibitor of DNA-PK. We found that DNA-PK deficient hypoxic cells are radiosensitive compared to hypoxic DNA-PK proficient cells and that this effect can be observed using both a small molecule inhibitor of DNA-PK, IC86621 (2), as well as with a genetically deficient model cell line. BCCA621C, which is designed to selectively release a DNA-PK inhibitor in hypoxic cells was synthesized and assessed for bioreduction using mouse liver microsomes and NCI-H460 cells. BCCA621C is activated by bioreduction in severely hypoxic NCI-H460 cells and was able to radiosensitize hypoxic NCI-H460 cells with a sensitizer enhancement ratio (SER) of 1.85. No enhancement of radiosensitivity was found to occur with BCCA621C treatment in oxygenated NCI-H460 cells in a range of clinically relevant ionizing radiation doses.
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