Alam Mohammad Maqusood, Wasim Sobia, Lee Sang-Yoon
Neuroscience Research Institute, Gachon University, Incheon 20565, Republic of Korea.
Department of Neuroscience, College of Medicine, Gachon University, Incheon 21936, Republic of Korea.
Int J Mol Sci. 2025 Jun 11;26(12):5582. doi: 10.3390/ijms26125582.
Targeted protein degradation (TPD) has emerged as a revolutionary strategy for modulating protein function, offering a promising alternative to traditional small-molecule inhibitors. The distinctive mechanism of action in TPD has previously allowed researchers to target undruggable proteins, broadening the scope of "druggable" properties and expanding the scope of therapeutic possibilities. As the field of TPD advances, several alternative strategies to proteolysis-targeting chimeras (PROTACs) have emerged, which do not rely on the E3 ubiquitin ligase recruitment mechanism, expending the scope of TPD. Recently, several new technologies have emerged for TPD of extracellular and membrane proteins. While encouraging progress has been made in this field, the application of these technologies remains in its early stages. In this review, we explore the therapeutic potential of current key emerging lysosome-mediated TPD approaches by summarizing key discoveries and address the challenges associated with degrading extracellular and membrane protein targets. We also outline the chemical structure, activity, and pharmaceutical properties of each degrader, as well as the development of chemical probes for perturbing autophagy pathways.
靶向蛋白质降解（TPD）已成为一种调节蛋白质功能的革命性策略，为传统小分子抑制剂提供了一种有前景的替代方案。TPD独特的作用机制此前使研究人员能够靶向难以成药的蛋白质，拓宽了“可成药”特性的范围，并扩大了治疗可能性的范围。随着TPD领域的发展，出现了几种不依赖E3泛素连接酶招募机制的靶向蛋白水解嵌合体（PROTAC）替代策略，扩大了TPD的范围。最近，出现了几种用于细胞外和膜蛋白TPD的新技术。虽然该领域已取得令人鼓舞的进展，但这些技术的应用仍处于早期阶段。在本综述中，我们通过总结关键发现来探索当前新兴的关键溶酶体介导的TPD方法的治疗潜力，并解决与降解细胞外和膜蛋白靶点相关的挑战。我们还概述了每种降解剂的化学结构、活性和药物性质，以及用于干扰自噬途径的化学探针的开发。
