The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound demonstrated robust radiosensitization of a broad range of cancer cells , displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c01120 | DOI Listing |
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