CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.

IF 2.9 4区医学 Q3 IMMUNOLOGY Immunopharmacology and Immunotoxicology Pub Date : 2024-08-01 Epub Date: 2024-07-04 DOI:10.1080/08923973.2024.2373223

Dan Li, Song Shan, Xuhua Mao, Yiru Zhao, Beizhong Chen, Qiuyun Xiong, Desi Pan, Shengjian Huang

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Abstract

Objective: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models.

Methods: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly.

Results: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor.

Conclusion: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.

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新型 JAK3/JAK1/TBK1 抑制剂 CS12192 可减轻小鼠模型中的自身免疫性皮肤病。

目的：自身免疫性皮肤病（AID）是指人体免疫系统攻击皮肤或组织，导致各种皮肤疾病或损伤。最近的研究表明，Janus 激酶（JAKs）通过调节多种细胞因子信号通路，在包括 AID 在内的自身免疫性疾病中发挥着关键作用。据报道，新型 JAK3/JAK1/TBK1 抑制剂 CS12192 对类风湿性关节炎有改善作用。然而，CS12192 对 AID 的疗效尚未确定。本研究旨在探讨 CS12192 在小鼠模型中对银屑病（PSO）、系统性红斑狼疮（SLE）和特应性皮炎（AD）的疗效：方法：白细胞介素 23（IL-23）诱导的 PSO 模型、MRL/MpJ-Faslpr/J（MRL/lpr）小鼠自发性系统性红斑狼疮模型以及恶唑酮（OXA）和二硝基氯苯（DNCB）诱导的小鼠 AD 模型分别用于评估 CS12192 的治疗效果。结果表明：在 PSO 模型中，CS12192 对小鼠的皮肤损伤、生化指标、耳厚、耳重和组织病理学进行了相应的评估：结果：在 PSO 模型中，用 CS12192 治疗的小鼠的耳厚和耳重都比用药物治疗的小鼠小。在系统性红斑狼疮模型中，CS12192 可改善淋巴结肿大和皮肤损伤等皮肤参数，但不能改善蛋白尿浓度和评分、血清 dsDNA 和 BUN 浓度等系统参数。在AD模型中，CS12192可剂量依赖性地改善耳部肿胀并降低组织学评分，其疗效与已上市的JAK1/JAK2抑制剂巴利昔尼相当。结论我们的研究结果表明，新型 JAK3/JAK1/TBK1 抑制剂 CS12192 有可能缓解自身免疫性皮肤病。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).