Abstract
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
MeSH terms
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Administration, Inhalation
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Animals
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Class Ia Phosphatidylinositol 3-Kinase / chemistry
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Crystallography, X-Ray
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Dogs
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Drug Evaluation, Preclinical
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ERG1 Potassium Channel / metabolism
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Hydrogen Bonding
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Isoquinolines / chemistry
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Madin Darby Canine Kidney Cells
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Phosphoinositide-3 Kinase Inhibitors*
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Rats
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Structure-Activity Relationship*
Substances
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ERG1 Potassium Channel
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Enzyme Inhibitors
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Isoquinolines
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KCNH2 protein, human
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Phosphoinositide-3 Kinase Inhibitors
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Class Ia Phosphatidylinositol 3-Kinase
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isoquinoline