Induced protein degradation for therapeutics: past, present, and future.
Induced protein degradation for therapeutics: past, present, and future.
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DOI：
10.1172/jci175265
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发表时间：
2024-01-02
影响因子：
15.9
通讯作者：
Ebert, Benjamin L.
中科院分区：
文献类型：
--
作者：
Yoon, Hojong;Rutter, Justine C.;Li, Yen -Der;Ebert, Benjamin L.
小分子诱导蛋白质降解的概念已经成为一种很有前途的治疗策略，对以前认为“不可药物”的蛋白质特别有效。用于治疗多发性骨髓瘤的沙利度胺类似物就是最好的例子。这些化合物作为分子胶，重定向CRBN E3泛素连接酶来降解骨髓瘤依赖因子IKZF1和IKZF3。沙利度胺类似物的临床成功证明了诱导蛋白质降解的治疗潜力。除了分子胶降解剂之外，还开发了其他几种触发蛋白质降解的方法，目前正在进行临床评估。这些包括异双功能降解物，聚合诱导降解，核激素受体的配体依赖性降解，蛋白质相互作用的破坏以及各种其他策略。在这篇综述中，我们将简要介绍各种降解方式，它们的临床应用，以及未来在蛋白质降解领域的潜在方向。
The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered “undruggable.” Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger protein degradation have been developed and are currently under clinical evaluation. These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.
DOI：
10.1016/j.crphar.2022.100138
发表时间：
2022
影响因子：
--
作者：
Andrews, Paul L R;Williams, Robin S B;Sanger, Gareth J
通讯作者：
Sanger, Gareth J