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通过PROTACs和其他策略进行蛋白质降解

Degradation of proteins by PROTACs and other strategies.

作者信息

Wang Yang, Jiang Xueyang, Feng Feng, Liu Wenyuan, Sun Haopeng

机构信息

Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.

Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.

出版信息

Acta Pharm Sin B. 2020 Feb;10(2):207-238. doi: 10.1016/j.apsb.2019.08.001. Epub 2019 Aug 13.

DOI:10.1016/j.apsb.2019.08.001
PMID:32082969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7016280/
Abstract

Blocking the biological functions of scaffold proteins and aggregated proteins is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be the solution, considering its ability to selectively degrade target proteins. Recent progress in the PROTAC strategy include identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this perspective, we summarized recent meaningful research of PROTAC, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases. Importantly, the molecular design, optimization strategy and clinical application of candidate molecules are highlighted in detail. Future perspectives for development of advanced PROTAC in medical fields have also been discussed systematically.

摘要

阻断支架蛋白和聚集蛋白的生物学功能是一个具有挑战性的目标。鉴于其能够选择性降解靶蛋白，蛋白水解靶向嵌合体（PROTAC）技术可能是解决方案。PROTAC策略的最新进展包括首个三元共晶复合物（BRD4-PROTAC-VHL）结构的鉴定，并且PROTAC ARV-110于2019年进入治疗前列腺癌的临床试验。这些发现有力地证明了PROTAC策略的价值。在此观点中，我们总结了PROTAC近期有意义的研究，包括降解蛋白的类型、体外和体内的初步生物学数据以及新的E3泛素连接酶。重要的是，详细强调了候选分子的分子设计、优化策略和临床应用。还系统地讨论了医学领域中先进PROTAC开发的未来前景。

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Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs).
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