Description
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 IC
50 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 IC
50 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.
References
1) Leahy?et al.?(2004),?Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries; Bioorg. Med. Chem. Lett.,?14?6083
2) Hardcastle?et al.?(2005),?Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach: J. Med. Chem.,?48?7829
3) Zhao?et al.?(2006),?Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441: Cancer Res.?66?5354
4) Ciszewski?et al.?(2014),?DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin: Breast Cancer Res. Treat.,?143?83
5) Yang?et al.?(2016),?NU7441 Enhances the Radiosensitivity of Liver Cancer Cells: Cell Physiol. Biochem.,?38?1897
6) Geng?et al.?(2019),?DNA-PKcs inhibitor increases the sensitivity of gastric cancer cells to radiotherapy: Oncol. Rep.,?42?561
