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Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries |
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| Authors: | Leahy Justin J J Golding Bernard T Griffin Roger J Hardcastle Ian R Richardson Caroline Rigoreau Laurent Smith Graeme C M |
| Affiliation: | aNorthern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK bKuDOS Pharmaceuticals Ltd, 327 Cambridge Science Park, Milton Rd, Cambridge CB4 4WG, UK |
| Abstract: | A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a highly potent and selective DNA-PK inhibitor (IC50 = 14 nM), exhibiting ATP-competitive inhibition kinetics. |
| Keywords: | Chromenones DNA repair DNA-PK Inhibitors |
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