Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide.
Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide.
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DOI：
10.1038/s41571-021-00479-z
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Ebert BL
中科院分区：
文献类型：
--
作者：
Jan M;Sperling AS;Ebert BL
几十年来，抗癌靶向治疗一直被设计为抑制激酶或其他酶类，并使许多患者受益匪浅。然而，需要新的方法来靶向转录因子、支架蛋白和其他对癌症生物学至关重要的蛋白质，这些蛋白质通常缺乏催化活性，并且对药物开发仍然具有很大的抗性。靶向蛋白的选择性降解是扩大可药物蛋白质组的一种有吸引力的方法，选择性雌激素受体降解剂氟维司汀是这一概念的早期例子。经过漫长而悲惨的临床历史，免疫调节亚胺药物（IMiD）沙利度胺被发现通过一种新的和意想不到的作用机制起作用：将蛋白质靶向E3泛素连接酶，随后进行蛋白酶体降解。这一发现平行并直接催化了药物开发的无数突破，导致了用于靶向降解以前无法药物的蛋白质的通用化学平台的快速成熟。几十年的临床经验已经确立了沙利度胺类似物在血液系统恶性肿瘤治疗中的一线作用。随着新一代“降解”药物目前正在开发中，这一经验为降解物的全类别特征提供了重要见解，包括独特的药理学、耐药机制和新兴的治疗机会。在此，我们回顾这些过去的经验，并讨论其在新型降解疗法的临床开发中的应用。
For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefitted many patients. Novel approaches are required, however, to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to act by a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalyzed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established frontline roles for thalidomide analogues in the treatment of haematological malignancies. With a new generation of ‘degrader’ drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.
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2.7
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