Abstract
Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.
MeSH terms
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Benzothiazoles / chemistry
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Benzothiazoles / metabolism
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Benzothiazoles / pharmacology*
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Class Ib Phosphatidylinositol 3-Kinase / chemistry
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Class Ib Phosphatidylinositol 3-Kinase / metabolism
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydrophobic and Hydrophilic Interactions
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Molecular Structure
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Binding
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Protein Structure, Tertiary
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Structure-Activity Relationship
Substances
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Benzothiazoles
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Enzyme Inhibitors
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Class Ib Phosphatidylinositol 3-Kinase
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PIK3CG protein, human
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benzothiazole