Ahn Jae-Hun, Kim Joohwan, Kwak Jina, Kim Jooil, Lee Na-Young, Choi Heejin, Bae Hee-Jin, Cho So-Hyun, Jung Sung-Gu, Kwon Hye-Mi, Kwon Euna, Kim Donghyun, Kim Myeongjoong, Yoon Daseul, Kim Seohyun, Kim Bongtae, Kang Byeong-Cheol
Department of Experiment Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
HK inno.N Corporation, Seoul, Republic of Korea.
Br J Pharmacol. 2025 Oct;182(20):5071-5082. doi: 10.1111/bph.70055. Epub 2025 May 7.
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.
The IC 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), 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.
IC values for IN-115314 and oclacitinib against JAK1-pSTAT3 were 9.4 and 61.3 nM, while IC 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 was -31.2% ± 30.7%, comparable with that of oclacitinib at doses of 0.4-0.6 mg·kg (-31.4% ± 15.8%).
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.
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.
JAK-STAT信号通路作为多种疾病的治疗靶点已受到广泛关注。本研究评估了新型小分子IN-115314对JAK-STAT通路的抑制作用。
在犬全血细胞和TF-1细胞中测定IN-115314对JAK1-pSTAT3和JAK2-pSTAT5的IC值。IN-115314通过灌胃给药（0.2至0.9mg·kg），而奥克拉替尼口服作为阳性对照。两种药物均每日给药两次，持续7天。分别在第1天和第7天分析药代动力学和药效学。
IN-115314和奥克拉替尼对JAK1-pSTAT3的IC值分别为9.4和61.3 nM，而对JAK2-pSTAT5的IC值分别为749和1214 nM。IN-115314的血浆浓度呈剂量依赖性增加且无蓄积，而奥克拉替尼在重复给药7天的过程中暴露量（相对于第1天的AUC）增加了1.65倍。在给予IN-115314后1至3小时，循环CD4 T淋巴细胞中离体IL-6诱导的pSTAT3激活受到最大抑制，0.45mg·kg剂量的IN-115314的抑制效力为-31.2%±30.7%，与0.4 - 0.6mg·kg剂量的奥克拉替尼（-31.4%±15.8%）相当。
总之，本研究证实了IN-115314对JAK-STAT的抑制作用，以及其药代动力学、药效学、安全性、有效性和最佳剂量的数据。我们预计IN-115314将被开发为一种用于治疗涉及JAK-STAT通路的各种疾病的新型治疗药物。
本文是主题为“代谢和慢性炎症性疾病中的药物和药物靶点”的特刊的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc。
