Background/Purpose:   The family of Janus kinases (JAKs) plays important roles in signaling pathway mediated by various cytokine receptors. An aberrant activation of JAK-STAT signaling has been reported to be involved in the pathogenesis of autoimmune diseases.Non-selective JAK inhibitors have shown excellent efficacy in patient with rheumatoid arthritis (RA). However, their use is limited due to adverse effects and safety concerns by inhibiting JAK1/2 signaling. Selective inhibition of JAK3 might result in an improved safety profile while maintaining excellent efficacy. The objectives of this study were to identify pharmacological profiles of TAS8274, a novel JAK3 inhibitor with high selectivity, and to evaluate its therapeutic potential in rat adjuvant-induced arthritis (AIA).

Methods:   In vitro biochemical assay was performed using available kinase assay panels. In cell-based assay, JAK3 activation was evaluated by interleukin (IL) -2-induced human peripheral blood mononuclear cells (PBMC) proliferation. IL-2–, IFN-α– and IL-3–induced phosphorylation of STAT proteins in PBMC were analyzed and quantified by a flow cytometry-based assay. Female Lewis rats were injected intradermally with adjuvant at the base of the tail. In order to evaluate the therapeutic efficacy of TAS8274 in rat AIA, treatment was initiated when the overt clinical signs of disease were observed. TAS8274 was administered orally twice daily for 2 weeks. Swelling in hind paws were measured using a plethysmometer. At the end of the experiment, the paws were removed to analyze the histopathological changes. The scoring of inflammation, pannus, cartilage and bone damage in two joints of the rat AIA was performed by a single blinded pathologist using a modified Mankin score system.

Results:   TAS8274 strongly inhibited the enzymatic activity of JAK3, and showed more than 1000-fold selectivity against other JAK family members, JAK1, JAK2 and TYK2. TAS8274 inhibited the IL-2–induced proliferation of PBMC in a dose dependent manner (IC₅₀ = 25.3 nM) and also potently suppressed IL-2–induced STAT5 phosphorylation (IC₅₀ = 18.9 nM). On the other hand, TAS8274 showed 300-3000 fold less inhibitory effects against JAK3–independent IFN-α or IL-3–induced STAT phosphorylation than that of JAK3–dependent STAT phosphorylation. In an established rat AIA, the hind paw volume in TAS8274-treated rats was dose-dependently decreased after oral administration of TAS8274 (0.3 to 10 mg/kg). TAS8274 also significantly reduced paw histopathology scores compared with those in vehicle-treated rats.

Conclusion:   Our results demonstrate that TAS8274 has the potential to elicit JAK3-mediated immunomodulatory effects without affecting the activities of JAK1, JAK2 and TYK2 and improves clinical signs of arthritis in the rat AIA. TAS8274 would be an attractive therapeutic agent for patients with autoimmune disorders such as RA, and reduce the side effects induced by inhibiting other JAK family members. TAS8274 was selected as a clinical candidate and is being evaluated for its safety profile to initiate Phase 1 study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tas8274-a-highly-selective-janus-kinase-3-inhibitor-demonstrates-potent-efficacy-in-an-animal-model-of-rheumatoid-arthritis/