Abstract
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
Keywords:
PI3Kδ; Phosphatidylinositol-3 kinases; Pyrrolo[2,1-f][1,2,4]triazin-4-amine; Rheumatoid arthritis.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Amines / chemistry*
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Amines / metabolism
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Amines / therapeutic use
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Animals
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Arthritis / drug therapy
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Arthritis / metabolism
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Arthritis / pathology
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Binding Sites
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Inhibitory Concentration 50
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Mice
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Molecular Docking Simulation
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Binding
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Structure-Activity Relationship
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Triazines / chemistry*
Substances
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Amines
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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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Triazines