Recent advances and future perspectives in small molecule JAK2 inhibitors

The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is essential for controlling immune function, blood cell formation, and cell growth. Dysregulation of this pathway is implicated in various diseases, including hematologic malignancies, autoimmune disorders, and chronic inflammatory conditions. This review provides a comprehensive overview of the structural and functional aspects of JAK/STAT signaling, with a particular focus on the role of JAK2. This manuscript explores the primary regulators of the JAK/STAT pathway, such as Suppressors Of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS), and Protein Tyrosine Phosphatases (PTPs), which play a crucial role in maintaining cellular balance and stability. Additionally, the therapeutic landscape of JAK2 inhibitors is explored, covering both approved and investigational drugs, including their mechanisms of action, efficacy, and safety profiles. Emerging strategies such as drug repositioning using computational approaches and experimental validation are also highlighted. By integrating insights from molecular docking studies, machine learning models, and kinase assays, this review emphasizes the potential of JAK2 inhibitors in disease management.

贾努斯激酶（Janus kinase, JAK）/信号转导与转录激活因子（Signal Transducer and Activator of Transcription, STAT）信号通路是调控免疫功能、血细胞生成与细胞生长的关键通路。该通路的失调与多种疾病密切相关，涵盖血液系统恶性肿瘤、自身免疫性疾病及慢性炎症性病症。本综述全面阐述了JAK/STAT信号通路的结构与功能特征，并重点聚焦JAK2的核心作用。本综述探讨了JAK/STAT通路的主要调控因子，包括细胞因子信号转导抑制因子（Suppressor Of Cytokine Signaling, SOCS）、活化STAT蛋白抑制剂（Protein Inhibitors of Activated STATs, PIAS）以及蛋白酪氨酸磷酸酶（Protein Tyrosine Phosphatases, PTPs）——这些因子在维持细胞稳态与稳定性中发挥关键作用。此外，本综述还梳理了JAK2抑制剂的治疗格局，涵盖已获批与在研药物，包括其作用机制、疗效与安全性特征。同时，本综述还重点介绍了新兴研发策略，例如基于计算方法的药物重定位及相关实验验证工作。通过整合分子对接研究、机器学习模型与激酶实验的相关研究进展，本综述强调了JAK2抑制剂在疾病管理中的应用潜力。