Abstract
A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Binding Sites
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Breast Neoplasms
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Female
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Gene Deletion
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Kinetics
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Models, Molecular
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / genetics
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Imidazoles
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyrimidinones
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Phosphatidylinositol 3-Kinase
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PTEN Phosphohydrolase
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PTEN protein, human