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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

Lookup NU author(s): Jonathan Hollick, Dr Laurent Rigoreau, Dr Celine Cano, Professor Nicola Curtin, Professor Bernard Golding, Sophie Guiard, Dr Ian Hardcastle, Professor Herbie Newell, Professor Roger Griffin

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Abstract

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. © 2007 American Chemical Society.


Publication metadata

Author(s): Hollick J, Rigoreau L, Cano-Soumillac C, Cockcroft X, Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR, Hickson I, Hummersone M, Menear K, Martin N, Matthews I, Newell DR, Ord R, Richardson C, Smith G, Griffin RJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2007

Volume: 50

Issue: 8

Pages: 1958-1972

Print publication date: 19/04/2007

Date deposited: 29/04/2010

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm061121y

DOI: 10.1021/jm061121y

PubMed id: 17371003


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