《生命科学》 2024, 36(2): 190-199

去泛素化酶USP1的结构、功能及其抑制剂的研究进展

徐亭亭 , 张　伟 , 敖　珍 , 李灵君^* , 吴　赟^*

药物成药性评价与系统转化全国重点实验室，天津药物研究院有限公司，朴创医药 科技(天津)有限公司，天津市新药设计与发现重点实验室，天津 300457

摘　要：

泛素化是一种维持细胞稳态必不可少的翻译后修饰，通过泛素分子与靶蛋白的连接参与蛋白质功能、定位和转换的调节。去泛素化酶介导的去泛素化为泛素化过程的逆反应，参与泛素的回收、编辑和重排。泛素特异性蛋白酶是最大的去泛素化酶家族，泛素特异性蛋白酶1 (USP1) 是其中重要的亚型，广泛参与维持基因组完整性、细胞周期和细胞稳态。在多种肿瘤类型中均存在USP1 异常表达，因此该靶点受到了广泛关注。目前研发进展最快的小分子USP1 抑制剂为KSQ-4279，处于I 期临床研究阶段；另外ISM3091 也已在国内和美国获得新药临床试验批件，即将开展临床试验。该文综述了USP1 的结构、调控、 生理功能、与肿瘤发生发展的关系以及USP1 抑制剂的研究进展。

通讯作者：李灵君 , Email:lilj@tipr.com.cn 吴　赟 , Email:wuy@tipr.com.cn

Advances in the study of structure, functions and inhibitors of deubiquitinating enzyme USP1

XU Ting-Ting , ZHANG Wei , AO Zhen , LI Ling-Jun^* , WU Yun^*

National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, Puchuang Pharmaceutical Technology (Tianjin) Co., Ltd., Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin 300457, China

Abstract:

Ubiquitination is an essential post-translational modification for maintaining cell homeostasis. Ubiquitination is involved in the regulation of protein function, localization and transformation by linking ubiquitin to target proteins. The process of deubiquitization mediated by deubiquitinating enzymes is the reverse reaction of ubiquitination and participates in the recovery, editing and rearrangement of ubiquitin. Ubiquitin-specific proteases are the largest family of deubiquitinating enzymes, and ubiquitin-specific processing peptidase 1 (USP1) is an important subtype of them. USP1 is widely involved in maintaining genome integrity, cell cycle and cell homeostasis. Abnormal expression of USP1 is found in multiple tumor types, so this target has received a lot of attention. At present, the small molecule USP1 inhibitor KSQ-4279 is the most advanced. It is in phase I clinical trial. ISM3091 has also obtained the clinical trial approval in China and the United States, and clinical trials will be carried out soon. In this paper, the structure, regulation, physiological function of USP1, the relationship between USP1 and tumorigenesis and the inhibitors of USP1 are reviewed.

Communication Author：LI Ling-Jun , Email:lilj@tipr.com.cn WU Yun , Email:wuy@tipr.com.cn