Abstract
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Computer Simulation
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Female
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Injections, Intravenous
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Liver / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mutation
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Structure, Tertiary
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tryptophan / chemistry*
Substances
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Phosphoinositide-3 Kinase Inhibitors
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Protein Isoforms
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Protein Kinase Inhibitors
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Tryptophan