Abstract
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Dogs
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Haplorhini
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Humans
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Mice
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Microsomes / drug effects
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Models, Molecular
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Molecular Structure
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Phosphatidylinositol 3-Kinases / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology*
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Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
Substances
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Enzyme Inhibitors
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Pyrazoles
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Pyridines
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pyrazolopyridine
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa