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Chemical Approaches to Intervening in Ubiquitin Specific Protease 7 (USP7) Function for Oncology and Immune Oncology Therapies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00498
Jian Wu 1 , Suresh Kumar 1 , Feng Wang 1 , Hui Wang 1 , Lijia Chen 1 , Patrick Arsenault 1 , Michael Mattern 1 , Joseph Weinstock 1
Affiliation  

Ubiquitin specific protease 7 (USP7), the most widely studied among the nearly 100 deubiquitinating enzymes, supports cancer by positively affecting tumor growth and negatively affecting the patient’s immune response to tumors. Great interest exists, therefore, in developing USP7 inhibitors for clinical evaluation. While the proteasome inhibitor field has enjoyed clinical success, very few clinically appropriate effectors of deubiquitinating (protease) or ubiquitinating (ligase) enzymes have appeared. The ubiquitin protease/ligase field is moving from the initial discovery of potent, selective modulators with cell proof of concept and in vivo activity to the optimization of these molecules to impart drug-like properties or the discovery of new inhibitor scaffolds by improved screening or rational design. This Perspective focuses on the current status of USP7 inhibitors from various organizations active in developing these compounds for the clinic and suggests undertakings that are both achievable and necessary to lead to successful clinical outcomes for USP7 inhibitors in cancer treatment.

中文翻译:

干预泛素特异性蛋白酶7(USP7)功能的化学方法在肿瘤学和免疫肿瘤学治疗中的作用

泛素特异性蛋白酶7(USP7)是近100种去泛素化酶中研究最广泛的一种,它通过积极影响肿瘤生长和消极影响患者对肿瘤的免疫反应来支持癌症。因此,对于开发用于临床评估的USP7抑制剂存在极大的兴趣。尽管蛋白酶体抑制剂领域已经取得了临床成功,但是很少出现临床上合适的去泛素化(蛋白酶)或泛素化(连接酶)酶的效应子。泛素蛋白酶/连接酶领域正在从最初发现具有细胞概念验证和体内有效,选择性调节剂的领域转移通过改进筛选或合理设计来优化这些分子以赋予药物样特性的活性或发现新的抑制剂支架。本观点着眼于活跃于临床开发这些化合物的各个组织的USP7抑制剂的现状,并提出了在癌症治疗中成功实现USP7抑制剂临床成果的既可实现又必要的任务。
更新日期:2017-08-18
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