School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Int Immunopharmacol. 2023 Sep;122:110660. doi: 10.1016/j.intimp.2023.110660. Epub 2023 Jul 19.
JAK kinase includes four family members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with signal transmitters and activators of subscription (STAT). This pathway is one of the main mechanisms by which many cytokine receptors transduce intracellular signals, it is associated with the occurrence of various immune, inflammatory, and tumor diseases. JAK inhibitors block the signal transduction of the JAK-STAT pathway by targeting JAK kinase. Based on whether they target multiple subtypes of JAK kinase, JAK inhibitors are categorized into pan-JAK inhibitors and selective JAK inhibitors. Compared with pan JAK inhibitors, selective JAK inhibitors are associated with a specific member, thus more targeted in therapy, with improved efficacy and reduced side effects. Currently, a number of JAK inhibitors have been approval for disease treatment. This review summarized the current application status of JAK inhibitors that have been marketed, advances of JAK inhibitors currently in phase Ш clinical trials, and the structure-activity relationship of them, with an intention to provide references for the development of novel JAK inhibitors.
JAK 激酶家族包括 JAK1、JAK2、JAK3 和 TYK2 四种。它与信号转导物和转录激活物（STAT）一起形成 JAK-STAT 通路。该通路是许多细胞因子受体转导细胞内信号的主要机制之一，与各种免疫、炎症和肿瘤疾病的发生有关。JAK 抑制剂通过靶向 JAK 激酶阻断 JAK-STAT 通路的信号转导。根据是否针对多种 JAK 激酶亚型，JAK 抑制剂可分为 pan-JAK 抑制剂和选择性 JAK 抑制剂。与 pan JAK 抑制剂相比，选择性 JAK 抑制剂针对特定成员，因此在治疗中更具针对性，疗效提高，副作用减少。目前，已有多种 JAK 抑制剂获批用于疾病治疗。本综述总结了已上市的 JAK 抑制剂的应用现状、目前处于Ш期临床试验阶段的 JAK 抑制剂的进展以及它们的构效关系，以期为新型 JAK 抑制剂的开发提供参考。
