2. Academic Validation
  3. 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

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

  • J Med Chem. 2007 Apr 19;50(8):1958-72. doi: 10.1021/jm061121y.
Jonathan J Hollick 1,  Laurent J M Rigoreau,  Celine Cano-Soumillac,  Xiaoling Cockcroft,  Nicola J Curtin,  Mark Frigerio,  Bernard T Golding,  Sophie Guiard,  Ian R Hardcastle,  Ian Hickson,  Marc G Hummersone,  Keith A Menear,  Niall M B Martin,  Ian Matthews,  David R Newell,  Rachel Ord,  Caroline J Richardson,  Graeme C M Smith,  Roger J Griffin
Affiliations

Affiliation

  • 1 Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.
PMID: 17371003 DOI: 10.1021/jm061121y
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-morpholino-pyran-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.

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