Abstract
By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Cutaneous
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Administration, Inhalation
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / toxicity
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Binding Sites
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Crystallography, X-Ray
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Dogs
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Drug Design
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Hepatocytes / metabolism
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Heterocyclic Compounds, 2-Ring / administration & dosage
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Heterocyclic Compounds, 2-Ring / toxicity
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Humans
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Indazoles / administration & dosage
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Indazoles / chemical synthesis
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Indazoles / pharmacology*
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Indazoles / toxicity
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Janus Kinase 1 / antagonists & inhibitors
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Janus Kinase 2 / antagonists & inhibitors
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Janus Kinase 3 / antagonists & inhibitors
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Janus Kinases / antagonists & inhibitors*
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Lung Diseases / drug therapy*
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / toxicity
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Rats
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Skin Diseases / drug therapy*
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Solubility
Substances
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Anti-Inflammatory Agents
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Heterocyclic Compounds, 2-Ring
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Indazoles
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PF-06263276
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Protein Kinase Inhibitors
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JAK1 protein, human
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JAK2 protein, human
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JAK3 protein, human
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Janus Kinase 1
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Janus Kinase 2
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Janus Kinase 3
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Janus Kinases