去泛素化酶USP7是多种肿瘤的生物标志物，其通过去泛素化作用使MDM2、DMNT1等致癌蛋白的稳定性增强，因而在肿瘤发生发展过程中发挥重要作用，被认为是极具前景的抗肿瘤新靶标。文献报道的USP7抑制剂活性和选择性均不够理想，至今尚未有任何分子进入临床研究。申请人近几年一直从事新型USP7抑制剂研究，我们通过分析USP7-泛素的复合晶体结构，发现USP7的泛素碳未端结合位点（位于催化域）是药物热点结合口袋，其Asp295等残基还参与了USP7-C端所介导的酶活化机制，因而可用于设计高效新型USP7抑制剂。前期研究针对该位点进行了虚拟筛选和实体化合物活性测试，发现3个具有一定选择性的USP7抑制剂先导化合物。在此基础上，本项目拟进一步开展新型先导化合物的发现、结构优化、生物活性评价及作用机制研究，以期获得活性强、选择性高且安全性好的新型USP7抑制剂，为肿瘤治疗提供新途径和候选药物分子。

The deubiquitinating enzyme USP7 is a biomarker of some tumors, and plays an important role in tumorigenesis and tumor development by enhancing the stability of key carcinogenic proteins such as MDM2 and DMNT1 by deubiquitination, and thus is regarded as a promising new anti-tumor target. However, the potency and selectivity of current USP7 inhibitors are not so good that by far there is not any inhibitor entering into clinical studies. In recent years, this applicant has been working on USP7 inhibitors. By analysis of crystallographic structures, we found that the ubiquitin C-terminal binding site (located at the catalytic domain) of USP7 was a drug-hot-binding pocket, and its residues such as Asp295 were also involved in the unique activation mechanism of USP7. We proposed that this site could be used to design novel and highly effective USP7 inhibitors. To this end, we conducted a virtual compound screening and activity test for the hits based on this site. As a result, three selective USP7 inhibitors were obtained. Based on this finding, this project will be focused on discovery of new lead compounds, structural modifications, biological evaluation, and mechanistic studies in order to find potent, selective and safe USP7 inhibitors. The project is expected to provide a breakthrough for the design of potent and highly selective USP7 inhibitors and to provide new avenues for cancer therapy and drug candidates.