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USP7 V517F mutation as a mechanism of inhibitor resistance

文献类型：期刊论文

作者Miao, Yu-Ling1; Fan, Fengying2,3; Cheng, Yong-Jun1; Jia, Li1,2; Song, Shan-Shan1,2; Huan, Xia-Juan1,2; Bao, Xu-Bin1,2; Ding, Jian1,2; Yu, Xuekui2,3; He, Jin-Xue1,2
刊名NATURE COMMUNICATIONS
出版日期2025-03-14
卷号16期号:1页码:14
DOI10.1038/s41467-025-56981-w
英文摘要Anticipating and addressing resistance is essential for maximizing the potential of an oncology target and effectively addressing clinical needs. In this study, we aimed to proactively outline the resistance mechanisms of USP7 inhibitors. We discovered a key treatment-emergent heterozygous mutation (V517F) in USP7 in the binding pocket of compounds as the primary cause of resistance to the USP7 inhibitor USP7-797. Our structural analysis, supported by AlphaFold2 predictions, indicates that the V517F mutation altered the conformation of the compound binding pocket, causing steric hindrance and reducing the affinity between USP7 and its inhibitors. Consistent with these predictions, the affinity between V517F mutant and USP7 inhibitors was found to reduce significantly. Conversely, substitutions at position V517 with smaller side chains, such as V517G, V517A, and V517I, do not significantly impact binding affinity. In contrast, replacement with the bulkier side chain V517Y leads to reduced binding affinity and diminished inhibitor efficacy. Furthermore, the engineered cell lines harboring the V517F mutation exhibited substantial resistance to USP7 inhibition. These data provide rationales for patient selection and the development of next-generation USP7 inhibitors designed to overcome treatment-emergent mutations.
WOS关键词POOR-PROGNOSIS ; HAUSP ; RECOGNITION ; DISCOVERY ; ENZYME ; POTENT ; P53
资助项目The National Key Research and Development Program of China (2022YFC3400500 to X.Y.)[82073875] ; National Natural Science Foundation of China ; State Key Laboratory of Drug Research[2022YFC3400500] ; National Key Research and Development Program of China
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001445493000005
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/316668]  
专题新药研究国家重点实验室
通讯作者Yu, Xuekui; He, Jin-Xue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Cryo Electron Microscopy Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Miao, Yu-Ling,Fan, Fengying,Cheng, Yong-Jun,et al. USP7 V517F mutation as a mechanism of inhibitor resistance[J]. NATURE COMMUNICATIONS,2025,16(1):14.
APA Miao, Yu-Ling.,Fan, Fengying.,Cheng, Yong-Jun.,Jia, Li.,Song, Shan-Shan.,...&He, Jin-Xue.(2025).USP7 V517F mutation as a mechanism of inhibitor resistance.NATURE COMMUNICATIONS,16(1),14.
MLA Miao, Yu-Ling,et al."USP7 V517F mutation as a mechanism of inhibitor resistance".NATURE COMMUNICATIONS 16.1(2025):14.

入库方式： OAI收割

来源：上海药物研究所

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