小分子Janus激酶抑制剂研究进展

Advances in Research on Small Molecule Janus Kinase Inhibitors

Janus激酶(JAK)属于非受体酪氨酸激酶,其与信号转导及转录激活因子(STAT)组成的JAK-STAT信号通路可影响细胞的增殖、分化、凋亡和免疫调节。自首个JAK抑制剂获批上市以来,小分子JAK抑制剂成为全球药物研发的热点。第1代JAK抑制剂为非选择性抑制剂,尽管取得了较好的疗效,但普遍因选择性不高在临床上表现出严重毒副作用。第2代JAK抑制剂为选择性抑制剂,能更加精准地调控细胞因子在JAK-STAT通路的信号转导,有效解决了第1代JAK抑制剂存在的安全性问题。对JAK结构、JAK-STAT通路作用机制及已上市和处于Ⅲ期临床试验阶段的JAK抑制剂研究进展进行综述,旨在为该类抑制剂的研发提供参考。

Janus kinase(JAK)is a non-receptor tyrosine kinase,and the JAK-signal transducer and activator of transcription(STAT)signaling pathway can affect cell proliferation,differentiation,apoptosis,and immunomodulation.Since the first JAK inhibitor was approved for marketing,small molecule JAK inhibitors have been a hotspot in global drug research and development.The first generation JAK inhibitors are non-selective inhibitors.Although they have achieved good therapeutic effects,they generally show severe toxic side effeets in clinical setting due to low sclectivity.The second generation JAK inhibitors are selective inhibitors.They can more acurately regulate the signal transduction of cytokines in the JAK-STAT pathway,thus ffectively solving the safety problems of the first-generation JAK inhibitors.This article has reviewed the structure of JAK,the action mechanisms of the JAK-STAT pathway,and the research progress of marketed JAK inhibitors and those in phase III clinical trials,aiming to provide references for the research and development of JAK inhibitors.