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Cross-Linking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space

文献类型：期刊论文

作者Xu, Yali2; Zhao, Wensi1,3; Nie, Hui-Jun2; Wang, Jiamin4; Fu, Jingjing5; Hu, Hao2; Liu, Zihao2; Tao, Shengna2; Zhang, Mingya2; Zhou, Yubo4,6
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2025-04-07
页码13
关键词Chemoproteomics Genetic code expansion Molecular glue degrader Photo-crosslinking Targeted protein degradation
DOI10.1002/anie.202505053
英文摘要Molecular glue (MG) degraders, small molecules with significant therapeutic potential for targeting undruggable proteins, are emerging as new modality in drug discovery. Profiling the E3 ligase interactome induced by MG degraders provides insights into their mechanism of action and identifies clinically relevant neosubstrates for degradation, thereby offering new therapeutic opportunities. However, established methods face significant challenges in comprehensive and accurate profiling of MG degrader-induced E3 ligase interactome. Herein, we introduce the concept of globally cross-linking profiling of the MG degrader-induced E3 ligase interactome in living cells, achieved by integrating genetic code expansion technology with mass spectrometry-based proteomics. Our approach presents an efficient and robust strategy for identifying neosubstrates recruited to cereblon E3 ligase by the known degraders CC-885 and DKY709, offering valuable insights for clinical evaluation and significantly expanding their target space. Moreover, we developed two novel MG degraders with potent antiproliferative effects on cancer cells, and application of our method identified neosubstrates, revealing a previously unrecognized target landscape and advancing our understanding of E3 ligase-neosubstrate interactions. Overall, our study provides a powerful tool for neosubstrate identification and expanding target space of E3 ligase, opening new opportunities for developing next-generation MG degraders to address the clinical challenge of undruggable targets.
WOS关键词PROTEIN-PROTEIN INTERACTIONS
资助项目National Science Foundation of China[22377136] ; National Science Foundation of China[22307126] ; National Science Foundation of China[22377133] ; National Science Foundation of China[22225702] ; National Science Foundation of China[T2488301] ; Shanghai Institute of Materia Medica[CASSIMM0120225001] ; Shanghai Sailing Program[23YF1456400] ; Zhongshan Science and Technology Bureau[CXTD2023009]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001460414600001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/316911]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Tan, Minjia; Chen, Xiao-Hua
作者单位1.Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai 200434, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Tongji Univ, Canc Ctr, Sch Med, Shanghai 200434, Peoples R China
4.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Yali,Zhao, Wensi,Nie, Hui-Jun,et al. Cross-Linking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2025:13.
APA Xu, Yali.,Zhao, Wensi.,Nie, Hui-Jun.,Wang, Jiamin.,Fu, Jingjing.,...&Chen, Xiao-Hua.(2025).Cross-Linking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,13.
MLA Xu, Yali,et al."Cross-Linking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2025):13.

入库方式： OAI收割

来源：上海药物研究所

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