Tyrosine kinase 2 inhibitors: Synthesis and applications in the treatment of autoimmune diseases

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2025-02-05 DOI:10.1016/j.ejmech.2024.117114

Lin Pan , Juan Xu , Hongming Xie , Yingjun Zhang , Huanfeng Jiang , Yongqi Yao , Wanqing Wu

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Abstract

Janus kinase (JAK), a class of non-receptor tyrosine kinases, are essential in modulating the cytokine signaling cascade of cytokines associated with immune responses. Despite their potential in the treatment of autoimmune diseases, JAK inhibitors are associated with safety concerns, regarding cytokine suppression and significant side effects. Tyrosine kinase 2 (TYK2), a prominent member of the JAK family, is central to the signaling of interleukins (ILs) and interferons (IFNs), such as IL-12, IL-23 and IFNs. Targeted TYK2 inhibitors that specifically target the Janus Homology 1 (JH1) and pseudokinase (JH2) domains show enhanced specificity. JH1 acts as an ATP-competitive inhibitor, while JH2 acts as an allosteric regulator, contributing to reduced systemic side effects and improved therapeutic outcomes in clinical settings. This review summarizes the recent advances on the synthetic strategies of TYK2 inhibitors and their applications in the treatment of autoimmune diseases.

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酪氨酸激酶2抑制剂的合成及其在自身免疫性疾病治疗中的应用

Janus激酶（JAK）是一类非受体酪氨酸激酶，在调节与免疫应答相关的细胞因子信号级联反应中起重要作用。尽管它们在自身免疫性疾病的治疗中具有潜力，但JAK抑制剂与安全性问题有关，涉及细胞因子抑制和显著的副作用。酪氨酸激酶2 （TYK2）是JAK家族的重要成员，对白细胞介素（il）和干扰素（ifn）（如IL-12、IL-23和ifn）的信号传导起着核心作用。特异性靶向Janus Homology 1 （JH1）和pseudokinase （JH2）结构域的TYK2抑制剂显示出增强的特异性。JH1作为atp竞争抑制剂，而JH2作为变构调节剂，有助于减少全身副作用并改善临床治疗效果。本文综述了TYK2抑制剂的合成策略及其在自身免疫性疾病治疗中的应用研究进展。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.