BCR::ABL1 酪氨酸激酶抑制剂 (TKI) 已将慢性粒细胞白血病 (CML) 从致命疾病转变为慢性疾病。通过最佳管理，慢性期诊断的 CML 患者的生存率已接近年龄匹配的对照组。然而，只有三分之一的患者可以停用 TKI 并进入称为无治疗缓解 (TFR) 的功能性治愈状态，而其余患者则需要终生 TKI 治疗以避免活动性白血病复发。大约 10% 的患者表现出原发性或获得性 TKI 耐药性，并最终进展至急变期。据认为，尝试 TFR 后的复发源于尽管 BCR::ABL1 激酶持续受到抑制，但 CML 干细胞 (LSC) 仍存活下来。尽管激酶活性对于诱导明显的 CML 是必不可少的，但已知 BCR::ABL1 的激酶独立支架功能有助于白血病的发生，这提出了一种有趣但尚未假设的可能性，即 BCR::ABL1 蛋白的降解可能会完成 TKI 所失败的任务实现 - 消除残留的 LSC，将功能性转化为真正的治疗方法。 BCR::ABL1 蛋白水解靶向嵌合体 (PROTAC) 的出现，将基于 TKI 的弹头与 E3 连接酶招募剂连接起来的异双功能分子，使临床蛋白质降解成为可能。在这里，我们研究了降解 BCR::ABL1 蛋白的分子原理以及优缺点。我们回顾了报告的 BCR::ABL1 PROTAC，指出了可用数据和化合物的局限性，并为未来的研究提出了方向。最终，需要对有效且特异性的 BCR::ABL1 降解剂进行临床测试，以确定该方法的功效和耐受性。© 2024。作者，获得 Springer Nature Limited 的独家许可。

BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve - eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.