Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

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Abstract

Abstract Objective All γ‐chain cytokines signal through JAK‐3 and JAK‐1 acting in tandem. We undertook this study to determine whether the JAK‐3 selective inhibitor WYE‐151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK‐1, JAK‐2, and Tyk‐2. Methods JAK‐3 kinase selective compounds were characterized by kinase assay and JAK‐3–dependent (interleukin‐2 [IL‐2]) and –independent (IL‐6, granulocyte–macrophage colony‐stimulating factor [GM‐CSF]) cell‐based assays measuring proliferation or STAT phosphorylation. In vivo, off‐target signaling was measured by IL‐22– and erythropoietin (EPO)–mediated models, while on‐target signaling was measured by IL‐2–mediated signaling. Efficacy of JAK‐3 inhibitors was determined using delayed‐type hypersensitivity (DTH) and collagen‐induced arthritis (CIA) models in mice. Results In vitro, WYE‐151650 potently suppressed IL‐2–induced STAT‐5 phosphorylation and cell proliferation, while exhibiting 10–29‐fold less activity against JAK‐3–independent IL‐6– or GM‐CSF–induced STAT phosphorylation. Ex vivo, WYE‐151650 suppressed IL‐2–induced STAT phosphorylation, but not IL‐6–induced STAT phosphorylation, as measured in whole blood. In vivo, WYE‐151650 inhibited JAK‐3–mediated IL‐2–induced interferon‐γ production and decreased the natural killer cell population in mice, while not affecting IL‐22–induced serum amyloid A production or EPO‐induced reticulocytosis. WYE‐151650 was efficacious in mouse DTH and CIA models. Conclusion In vitro, ex vivo, and in vivo assays demonstrate that WYE‐151650 is efficacious in mouse CIA despite JAK‐3 selectivity. These data question the need to broadly inhibit JAK‐1–, JAK‐2–, or Tyk‐2–dependent cytokine pathways for efficacy.

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