Abstract
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Drug Discovery
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Humans
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Models, Molecular
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazines / chemistry*
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Pyrazines / pharmacology*
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Signal Transduction / drug effects
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrazines
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases