Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries

• Published in: Bioorganic & medicinal chemistry letters 2004-12, Vol.14 (24), p.6083-6087
• Main Authors: Leahy, Justin J.J., Golding, Bernard T., Griffin, Roger J., Hardcastle, Ian R., Richardson, Caroline, Rigoreau, Laurent, Smith, Graeme C.M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chromenones; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; DNA repair; DNA-Activated Protein Kinase; DNA-Binding Proteins - antagonists & inhibitors; DNA-PK; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitors; Medical sciences; Miscellaneous; Molecular Structure; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.09.060

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 (IC 50 = 14 nM), exhibiting ATP-competitive inhibition kinetics. 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 (IC 50 = 14 nM), exhibiting ATP-competitive inhibition kinetics.