Song Yihui, Ren Xiangli, Xiong Jinbo, Wang Wenwen, Zhao Qianyan, Chang Junbiao, Yu Bin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, 350122, China.
J Med Chem. 2025 Apr 24;68(8):7914-7931. doi: 10.1021/acs.jmedchem.5c00102. Epub 2025 Apr 16.
Protein ubiquitination is a reversible post-translational modification regulated by ubiquitin-conjugating and deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 7 (USP7), a well-characterized DUB, plays multifaceted roles in various cellular processes, making it a promising therapeutic target. The plasticity of its catalytic domain and unique allosteric regulation by substrates or external or intramolecular factors facilitate the identification of highly selective USP7 inhibitors. These inhibitors can engage distinct ubiquitin-binding sites through covalent or non-covalent mechanisms. Despite its therapeutic promise, no USP7 inhibitors have entered clinical trials, underscoring the urgent need for novel therapeutics. Here we provide a crystallographic and functional landscape of USP7's multilayer regulation and analyze the structure-activity relationship of inhibitors by chemotypes. Additionally, we explore USP7's roles in diseases and discuss the challenges in USP7-targeted drug discovery and future directions for therapeutic development. This Perspective aims to provide a systematic overview of USP7, from its regulatory mechanisms to its therapeutic potential.
蛋白质泛素化是一种由泛素结合酶和去泛素化酶（DUBs）调节的可逆性翻译后修饰。泛素特异性蛋白酶7（USP7）是一种特征明确的DUB，在各种细胞过程中发挥多方面作用，使其成为一个有前景的治疗靶点。其催化结构域的可塑性以及底物、外部或分子内因素对其独特的变构调节，有助于鉴定高度选择性的USP7抑制剂。这些抑制剂可通过共价或非共价机制结合不同的泛素结合位点。尽管USP7抑制剂具有治疗前景，但尚无此类抑制剂进入临床试验，这凸显了对新型疗法的迫切需求。在此，我们提供了USP7多层调节的晶体学和功能概况，并按化学类型分析了抑制剂的构效关系。此外，我们探讨了USP7在疾病中的作用，并讨论了USP7靶向药物研发面临的挑战以及治疗开发的未来方向。本观点旨在提供对USP7的系统概述，从其调节机制到治疗潜力。
