Department of Pharmacodynamics, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL 32610, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL 32610, USA.
Future Med Chem. 2020 Jun;12(12):1155-1179. doi: 10.4155/fmc-2020-0073. Epub 2020 May 20.
Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure-activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.
小分子降解剂靶向蛋白降解代表了药物发现中一种新兴的作用模式。蛋白水解靶向嵌合体（PROTACs）是一种小分子，可以募集 E3 连接酶和目标蛋白（POI）接近，导致 POI 通过蛋白酶体系统诱导泛素化和降解。迄今为止，由于诱导蛋白降解的复杂机制，PROTACs 的设计和优化仍然是经验性的。然而，越来越多的人认识到，使用生化和生物物理测定法沿着泛素-蛋白酶体降解途径逐步进行剖析对于理解结构-活性关系和促进 PROTACs 的合理设计至关重要。本综述旨在总结这些测定法，并讨论用其他新技术扩展工具箱的潜力。
