Abstract
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1β production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.
Trial registration:
ClinicalTrials.gov NCT02309827.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / immunology
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Disease Models, Animal
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Drug Discovery
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Humans
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Interleukin-10 / immunology
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Interleukin-1beta / immunology
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Janus Kinase 1 / antagonists & inhibitors
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Janus Kinase 1 / metabolism
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Janus Kinase 3 / antagonists & inhibitors*
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Janus Kinase 3 / metabolism
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Models, Molecular
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Pyrroles / therapeutic use*
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Rats
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Th1 Cells / cytology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th17 Cells / cytology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Tumor Necrosis Factor-alpha / immunology
Substances
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Interleukin-1beta
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PF-06651600
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Janus Kinase 1
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Janus Kinase 3
Associated data
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ClinicalTrials.gov/NCT02309827