DNA-dependent protein kinase (DNA-PK) catalyzes nonhomologous end-joining, which is required to repair lethal DNA double-strand breaks. Because cells that are defective in DNA double-strand break repair are highly sensitive to ionizing radiation and topoisomerase II poisons, modulating DNA-PK is one strategy to defer cancer cell resistance to radiation or chemotherapeutic treatments. NU 7441 is a selective DNA-PK inhibitor with an IC50 value of 14 nM. It inhibits other members of the PI3K-related kinase family, including mTOR, PI3K, ataxia telangiectasia mutated (ATM), and ataxia telangiectasia and Rad3 related (ATR) with IC50 values of 1.7, 5, >100, and >100 μM, respectively. NU 7441 has been shown to increase the cytotoxicity of ionizing radiation and etoposide in human colon cancer cell lines in vitro and to potentiate the effects of etoposide in mice bearing human colon cancer xenograft tumors in vivo.
