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.
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.
Hollick
Jonathan J
JJ
Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.
Rigoreau
Laurent J M
LJ
Cano-Soumillac
Celine
C
Cockcroft
Xiaoling
X
Curtin
Nicola J
NJ
Frigerio
Mark
M
Golding
Bernard T
BT
Guiard
Sophie
S
Hardcastle
Ian R
IR
Hickson
Ian
I
Hummersone
Marc G
MG
Menear
Keith A
KA
Martin
Niall M B
NM
Matthews
Ian
I
Newell
David R
DR
Ord
Rachel
R
Richardson
Caroline J
CJ
Smith
Graeme C M
GC
Griffin
Roger J
RJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005047:Etoposide; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011714:Pyrans; D011728:Pyridones; D011753:Pyrones; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins; C520347:2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one; C576324:ATM protein, human