药学学报, 2022, 57(3): 547-556
引用本文:
刘湘宁#, 杜佳泯#, 钱美佳, 董晓武, 杨波, 朱虹*, 何俏军*. 去泛素化酶小分子抑制剂抗肿瘤作用研究:新进展和新思路[J]. 药学学报, 2022, 57(3): 547-556.
LIU Xiang-ning#, DU Jia-min#, QIAN Mei-jia, DONG Xiao-wu, YANG Bo, ZHU Hong*, HE Qiao-jun*. Research on antitumor effects of small molecule inhibitors of deubiquitinases: new progress and new ideas[J]. Acta Pharmaceutica Sinica, 2022, 57(3): 547-556.

去泛素化酶小分子抑制剂抗肿瘤作用研究:新进展和新思路
刘湘宁#, 杜佳泯#, 钱美佳, 董晓武, 杨波, 朱虹*, 何俏军*
浙江大学药学院, 浙江 杭州 310058
摘要:
泛素-蛋白酶体通路异常是导致蛋白质内稳态失控的重要因素。而在该过程中,负责移除蛋白底物泛素链的去泛素化酶至关重要,其活性或表达异常可造成关键致癌/抑癌蛋白的功能变化,直接或间接导致肿瘤发生发展和恶性演进。基于此,靶向去泛素化酶的小分子抑制剂发现及研究已经成为抗肿瘤候选药物的热点领域之一。本综述将重点介绍泛素-蛋白酶体通路、尤其是去泛素化酶对肿瘤的调控作用和机制,介绍去泛素化酶小分子抑制剂在肿瘤治疗研究中的应用,并针对小分子抑制剂的研究现状和最新进展展开讨论,为基于去泛素化酶的抗肿瘤新策略研究提供思路。
关键词:    泛素-蛋白酶体通路      去泛素化酶      去泛素化酶抑制剂      抗肿瘤新靶点      变构调节     
Research on antitumor effects of small molecule inhibitors of deubiquitinases: new progress and new ideas
LIU Xiang-ning#, DU Jia-min#, QIAN Mei-jia, DONG Xiao-wu, YANG Bo, ZHU Hong*, HE Qiao-jun*
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
The abnormality of ubiquitin proteasome pathway is an important factor leading to the imbalance of protein homeostasis. In this process, the deubiquitinase responsible for removing the ubiquitin chain of protein substrate is very important. Its abnormal activity or expression can cause the functional changes of key oncogenic/tumor suppressor proteins, which directly or indirectly lead to the occurrence, development and malignant evolution of tumors. Based on this, the discovery and research of small molecule inhibitors targeting deubiquitinases have become a hot field of anti-tumor candidate drugs. This review will focus on the regulatory effect and mechanism of ubiquitin proteasome pathway, especially deubiquitinase on tumor, introduce the application of deubiquitinase small molecule inhibitors in tumor treatment, and discuss the research status and latest progress of small molecule inhibitors, so as to provide ideas for the research of new anti-tumor strategies based on deubiquitinase.
Key words:    ubiquitin proteasome pathway    deubiquitinase    deubiquitinase inhibitor    new anti-tumor target    allosteric regulation   
收稿日期: 2021-07-28
DOI: 10.16438/j.0513-4870.2021-1118
基金项目: 国家自然科学基金资助项目(81973349);浙江省自然科学基金资助项目(LR19H310002)。
通讯作者: 朱虹,Tel:86-571-88208401,E-mail:hongzhu@zju.edu.cn;何俏军,Tel:86-571-88208400,E-mail:qiaojunhe@zju.edu.cn
Email: hongzhu@zju.edu.cn;qiaojunhe@zju.edu.cn
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