JAK–STAT inhibitory effect of IN‐115314, a novel small molecule inhibitor, and pharmacokinetic/pharmacodynamic study in canine

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Background and Purpose The JAK–STAT signalling pathway has been extensively spotlighted as a therapeutic target for various diseases. This study assessed the inhibitory effects of a novel small molecule, IN‐115314, on JAK–STAT pathway. Experimental Approach The IC50 values of IN‐115314 for JAK1–pSTAT3 and JAK2–pSTAT5 were determined in canine whole blood cells and TF‐1 cells. IN‐115314 administered intragastrically (0.2 to 0.9 mg·kg−1), while oclacitinib was given orally as a positive control. Both drugs were administered twice daily for 7 days. Pharmacokinetics and pharmacodynamics were analysed on Days 1 and 7, respectively. Key Results IC50 values for IN‐115314 and oclacitinib against JAK1–pSTAT3 were 9.4 and 61.3 nM, while IC50 values against JAK2–pSTAT5 were 749 and 1214 nM, respectively. Plasma concentrations of IN‐115314 increased in a dose‐dependent manner without accumulation, whereas oclacitinib displayed a 1.65‐fold increase in exposure (AUC relative to Day 1) across 7 days of repeated dosing. The ex vivo IL‐6‐induced pSTAT3 activation in circulating CD4+ T lymphocytes was maximally suppressed between 1 and 3 h after administration of IN‐115314, and the inhibitory efficacy of IN‐115314 at a dose of 0.45 mg·kg−1 was −31.2% ± 30.7%, comparable with that of oclacitinib at doses of 0.4–0.6 mg·kg−1 (−31.4% ± 15.8%). Conclusion and Implications In summary, this study confirmed IN‐115314 JAK–STAT inhibitory effect, along with data on its pharmacokinetics, pharmacodynamics, safety, efficacy and optimal dosage. We anticipate that IN‐115314 will be developed as a new therapeutic agent for various diseases involving the JAK–STAT pathway. LINKED ARTICLES This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc