935700-59-7Relevant articles and documents
Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase
Hollick, Jonathan J.,Rigoreau, Laurent J. M.,Cano-Soumillac, Celine,Cockcroft, Xiaoling,Curtin, Nicola J.,Frigerio, Mark,Golding, Bernard T.,Guiard, Sophie,Hardcastle, Ian R.,Hickson, Ian,Hummersone, Marc G.,Menear, Keith A.,Martin, Niall M. B.,Matthews, Ian,Newell, David R.,Ord, Rachel,Richardson, Caroline J.,Smith, Graeme C. M.,Griffin, Roger J.
, p. 1958 - 1972 (2008/02/02)
Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholinopyran-4-ones and 2-morpholino- thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6- (morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = 220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.
