Cardno Annabel, Kennedy Bryony, Lindon Catherine
Department of Pharmacology, University of Cambridge, Cambridge, UK.
Commun Biol. 2025 May 2;8(1):691. doi: 10.1038/s42003-025-08104-w.
In recent years the development of proteolysis-targeting chimeras (PROTACs) has enhanced the field of ubiquitin signalling through advancing therapeutic targeted protein degradation (TPD) strategies and generating tools to explore the ubiquitin landscape. However, the interplay between PROTACs and their substrates, and other components of the ubiquitin proteasome system (UPS), raises fundamental questions about cellular parameters that might influence the action of PROTACs and the amenability of a given target to PROTAC-mediated degradation. In this perspective we discuss examples of cellular parameters that have been shown to influence PROTAC sensitivity and consider others likely to be important for PROTAC-mediated target degradation but not yet routinely considered in design of novel TPD strategies: Target localisation and accessibility on the one hand, and expression patterns, localisation and activity of E3 ligases, deubiquitinases (DUBs) and wider ubiquitin machinery on the other, are critical parameters in the exploitation of PROTACs, and establishing a better understanding of these parameters will facilitate the rational design of PROTACs.
近年来，靶向蛋白降解嵌合体（PROTACs）的发展通过推进治疗性靶向蛋白降解（TPD）策略以及生成探索泛素格局的工具，增强了泛素信号传导领域。然而，PROTACs与其底物以及泛素蛋白酶体系统（UPS）的其他组分之间的相互作用，引发了关于可能影响PROTACs作用以及给定靶点对PROTAC介导降解的适应性的细胞参数的基本问题。从这个角度出发，我们讨论了已被证明会影响PROTAC敏感性的细胞参数示例，并考虑了其他可能对PROTAC介导的靶点降解很重要但在新型TPD策略设计中尚未常规考虑的参数：一方面是靶点的定位和可及性，另一方面是E3连接酶、去泛素化酶（DUBs）和更广泛的泛素机制的表达模式、定位和活性，这些都是利用PROTACs的关键参数，更好地理解这些参数将有助于PROTACs的合理设计。
