Cheng Binbin, Li Hongqiao, Peng Xiaopeng, Chen Jianjun, Shao Chuxiao, Kong Zhihua
Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University, Huangshi, 435003, China; Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, Lishui, Zhejiang, 323000, China.
The Central Hospital of Huangshi, Huangshi, 435000, China.
Eur J Med Chem. 2025 Feb 15;284:117212. doi: 10.1016/j.ejmech.2024.117212. Epub 2024 Dec 27.
Targeted protein degradation (TPD) represents a promising therapeutic approach, encompassing several innovative strategies, including but not limited to proteolysis targeting chimeras (PROTACs), molecular glues, hydrophobic tag tethering degraders (HyTTD), and lysosome-targeted chimeras (LYTACs). Central to TPD are small molecule ligands, which play a critical role in mediating the degradation of target proteins. This review summarizes the current landscape of small molecule ligands for TPD molecules. These small molecule ligands can utilize the proteasome, lysosome, autophagy, or hydrophobic-tagging system to achieve the degradation of target proteins. The article mainly focuses on introducing their design principles, application advantages, and potential limitations. A brief discussion on the development prospects and future directions of TPD technology was also provided.
靶向蛋白质降解（TPD）是一种很有前景的治疗方法，涵盖了多种创新策略，包括但不限于蛋白酶靶向嵌合体（PROTAC）、分子胶、疏水标签连接降解剂（HyTTD）和溶酶体靶向嵌合体（LYTAC）。TPD的核心是小分子配体，它们在介导靶蛋白降解中起关键作用。本综述总结了TPD分子小分子配体的当前情况。这些小分子配体可利用蛋白酶体、溶酶体、自噬或疏水标签系统来实现靶蛋白的降解。本文主要着重介绍其设计原理、应用优势及潜在局限性。还对TPD技术的发展前景和未来方向进行了简要讨论。
