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

Jonathan J Hollick; 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

doi:10.1021/jm061121y

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. Epub 2007 Mar 20.

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.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Combinatorial Chemistry Techniques
DNA-Activated Protein Kinase / antagonists & inhibitors*
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / chemistry
Etoposide / pharmacology
HeLa Cells
Humans
Morpholines / chemical synthesis*
Morpholines / chemistry
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / chemistry*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Pyrans / chemical synthesis*
Pyrans / chemistry
Pyrans / pharmacology
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacology
Pyrones / chemical synthesis*
Pyrones / chemistry
Pyrones / pharmacology
Structure-Activity Relationship
Topoisomerase II Inhibitors
Tumor Suppressor Proteins / antagonists & inhibitors*
Tumor Suppressor Proteins / chemistry

Substances

2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one
Antineoplastic Agents
Cell Cycle Proteins
DNA-Binding Proteins
Morpholines
Pyrans
Pyridones
Pyrones
Topoisomerase II Inhibitors
Tumor Suppressor Proteins
Etoposide
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
DNA-Activated Protein Kinase
Protein Serine-Threonine Kinases