骨髓增生性肿瘤 (MPN) 是一种罕见的造血系统疾病，由 JAK-STAT 信号通路基因突变驱动。虽然 JAK2 抑制剂已经改变了 MPN 治疗，但它们并不能消除大多数患者的恶性克隆或阻止疾病进展。这一局限性强调了对更有效疗法的需求。这篇综述研究了用于治疗 MPN 的 JAK2 抑制剂的进展。目前的 JAK2 抑制剂主要作为 I 型抑制剂，针对活性激酶构象，但其有效性受到持续的 JAK-STAT 信号传导的限制。为了克服这些限制，正在开发下一代疗法，例如 II 型 JAK2 抑制剂和假激酶结构域抑制剂，以针对非活性激酶构象和替代信号通路。此外，正在研究 PI3K、mTOR、CDK4/6 抑制剂和表观遗传调节剂的联合疗法的潜在协同效应，旨在为 MPN 患者带来更深入、更持久的反应。需要下一代 JAK2 抑制剂来增强当前的 MPN 治疗克服耐药性，提高选择性，针对特定患者群体，并探索联合疗法。解决药物设计、临床前测试和临床试验中的挑战至关重要。迫切需要开发针对 JAK2 和其他 MPN 相关通路的双重或多重抑制剂，以解决复杂的信号网络并提高疗效。

Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective therapies.This review examines the evolution of JAK2 inhibitors for treating MPNs. Current JAK2 inhibitors primarily function as type I inhibitors, targeting the active kinase conformation, but their effectiveness is limited by ongoing JAK-STAT signaling. To overcome these limitations, next-generation therapies, such as type II JAK2 inhibitors and pseudokinase domain inhibitors, are being developed to target inactive kinase conformations and alternative signaling pathways. Furthermore, combination therapies with PI3K, mTOR, CDK4/6 inhibitors, and epigenetic modulators are being investigated for their potential synergistic effects, aiming for deeper and more durable responses in MPN patients.Next-generation JAK2 inhibitors are needed to enhance current MPNs treatments by overcoming resistance, improving selectivity, targeting specific patient groups, and exploring combination therapies. Addressing challenges in drug design, preclinical testing, and clinical trials is crucial. Developing dual or multiple inhibitors targeting JAK2 and other MPN-related pathways is urgent to address complex signaling networks and improve efficacy.