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

Abstract

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.

Figure 1

Chemical structure of oclacitinib. Oclacitinib is a cyclohexylamino pyrrolopryimidine.

Figure 2

Cytokine receptor families that utilize Janus kinase (JAK) enzymes for signaling. Cytokines are small proteins secreted by cells that can produce a variety of responses such as growth, development, differentiation, and activation of immune cells as well as nonimmune cell types. Cytokines exert these biological effects by binding to receptors on the surface of cells. Several cytokine receptors rely on the association and activation of JAK enzymes on the cytoplasmic portion of the receptor in order to transmit signals to the nucleus and induce necessary changes within the cell. Cytokine receptors can be groups according to the types of JAKs that are recruited to the receptor complexes. Many cytokines involved in allergy, inflammation, and pruritus bind receptor complexes that utilize JAK1. For example, IL-2 and IL-4 will bind receptor complexes that recruit JAK1 and JAK3. IL-6 and IL-13 bind receptors that engage JAK1, JAK2, and TYK2, and IL-31 will engage receptors that activate JAK1 and JAK2. In contrast, several cytokines involved in hematopoiesis (GM-CSF, erythropoietin) or innate immune cell defenses (IL-12 and IL-23) activate receptors dependent on JAK2/JAK2 or JAK2/TYK2 pairings.