Oclacitinib (APOQUEL®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy

Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using...

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Bibliographic Details
Published in:Journal of veterinary pharmacology and therapeutics 2014-08, Vol.37 (4), p.317-324
Main Authors: Gonzales, A. J, Bowman, J. W, Fici, G. J, Zhang, M, Mann, D. W, Mitton‐Fry, M
Format: Article
Language:English
Subjects:
Animals
Cytokines - antagonists & inhibitors
Cytokines - genetics
Cytokines - metabolism
Dermatologic Agents - chemistry
Dermatologic Agents - pharmacology
dogs
Dogs - blood
Enzymes - blood
erythropoietin
Gene Expression Regulation - drug effects
Humans
hypersensitivity
inflammation
inhibitory concentration 50
Janus Kinases - antagonists & inhibitors
Molecular Structure
non-specific protein-tyrosine kinase
pruritus
Pyrimidines - chemistry
Pyrimidines - pharmacology
Scientific Papers
signal transduction
skin diseases
Sulfonamides - chemistry
Sulfonamides - pharmacology
therapeutics
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Summary:Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC₅₀'s) ranging from 10 to 99 nm and did not inhibit a panel of 38 non‐JAK kinases (IC₅₀'s > 1000 nm). Oclacitinib was most potent at inhibiting JAK1 (IC₅₀ = 10 nm). Oclacitinib also inhibited the function of JAK1‐dependent cytokines involved in allergy and inflammation (IL‐2, IL‐4, IL‐6, and IL‐13) as well as pruritus (IL‐31) at IC₅₀'s ranging from 36 to 249 nm. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony‐stimulating factor, IL‐12, IL‐23; IC₅₀'s > 1000 nm). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1‐dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.
ISSN:0140-7783
1365-2885
DOI:10.1111/jvp.12101