Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, 250014, China.
College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
Eur J Med Chem. 2023 Dec 5;261:115839. doi: 10.1016/j.ejmech.2023.115839. Epub 2023 Sep 27.
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
靶向蛋白降解（TPD）作为一种有前途的治疗方法已经出现，与传统基于占位的抑制剂相比，它在给药、副作用和靶向“不可成药”蛋白方面具有潜在优势。靶向降解剂理论上可以结合靶蛋白的任何角落和缝隙来驱动降解。与必须在明确口袋中发挥作用的小分子抑制剂相比，这更具便利性。降解过程主要取决于两种细胞自毁机制，即泛素-蛋白酶体系统和溶酶体降解途径。已经开发了各种 TPD 策略（例如，蛋白水解靶向嵌合体、分子胶、溶酶体靶向嵌合体和自噬靶向嵌合体）。这些方法在靶向失调蛋白方面具有很大的潜力，可能提供治疗益处。在本文中，我们系统地综述了各种 TPD 策略的机制、在药物发现中的潜在应用以及最新进展。我们还讨论了这些 TPD 策略的益处和挑战，旨在深入了解失调蛋白的靶向并促进其临床应用。
