Sun Donghuan, Zhang Jing, Dong Guoqiang, He Shipeng, Sheng Chunquan
School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
Department of Pathology, Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai 200003, China.
J Med Chem. 2022 Nov 10;65(21):14276-14288. doi: 10.1021/acs.jmedchem.2c01159. Epub 2022 Oct 28.
The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.
靶蛋白的非酶功能在各种细胞信号通路的调控中发挥着关键作用，并且与众多人类疾病密切相关。然而，传统的小分子抑制剂通常直接靶向催化功能域，通过抑制靶蛋白的酶功能起作用，而不影响其非酶功能。最近新兴的蛋白酶靶向嵌合体（PROTAC）技术具有同时调节靶蛋白的酶功能和非酶功能的优势，从而提供了一种潜在策略来弥补抑制剂的不足，并通过靶蛋白降解探索新的治疗模式。本综述旨在具体总结和分析PROTAC介导的降解阻断靶蛋白非酶功能的最新进展，突出代表性案例研究，并讨论源于抑制非酶功能的药理学特征。
