Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs
Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs
复制标题
针对 Cullin-RING 泛素连接及其在 PROTAC 中的应用。
DOI：
10.1007/978-981-15-1025-0_19
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发表时间：
2020-01-01
期刊：
影响因子：
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通讯作者：
Zhao, Yongchao
中科院分区：
文献类型：
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作者：
Gong, Longyuan;Cui, Danrui;Zhao, Yongchao
作为E3泛素连接酶家族中最大的一类，库林-环连接酶(CRL)能够调节多种功能和结构上不同的蛋白质的降解，从而控制多种生物过程，已成为药物开发的重要靶点。由于CRL及其底物蛋白的异常表达与人类疾病有关，阐明它们在这些生理和病理过程中的作用将有助于CRL靶向药物的开发。值得注意的是，这些研究还为设计潜在的针对CRLS的小分子疗法以及使用CRLS降解“不可用药”的蛋白质提供了新的概念。在本章中，我们系统地回顾了靶向CRLS的小分子的发展，特别是CRLS在蛋白质降解的化学嵌合体中的应用，称为蛋白质降解靶向嵌合体(PROTACs)。
Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, have become an attractive target for drug discovery, primarily due to their ability to regulate the degradation of numerous functionally and structurally diverse proteins, thereby controlling a myriad of biological processes. As the abnormal expressions of CRLs and their substrate proteins are associated with human diseases, elucidating their roles in these physiological and pathological processes will facilitate CRL-targeting drug development for the treatment of these diseases. Notably, these studies are also providing new concepts for the design of potential small-molecule therapeutics targeting CRLs and for the use of CRLs to degrade “undruggable” proteins. In this chapter, we systematically review the development of small molecules that target CRLs and especially emphasize the applications of CRLs in a chemical chimera for protein degradation, termed proteolysis-targeting chimeras (PROTACs).