DNA-dependent protein kinase (DNA-PK) is involved in the non-homologous end-joining pathway of DNA double strand breaks (DSBs). DSBs can be initiated by ionising radiation or chemotherapy.1 ATP-competitive inhibitors of DNA-PK could potentiate the effects of these cancer therapies. Inhibitor design was guided by the non-selective PIKK inhibitor, LY294002. Lead compound NU7441 was hampered by sub-optimal pharmaceutical properties.2 Synthesis of 7-, 8- and 9-substituted dibenzothiophene inhibitors provided water-soluble compounds with retained potency.References Nature, 2001, 411  , 366.J. Med. Chem., 2005, 48  , 7829.

Development of potent inhibitors of DNA-dependent protein kinase (DNA-PK)

245th National Meeting (2013)

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