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Fluorescence-Coupled Ubiquitination Assay as a High-Throughput Screening Strategy for Novel Cereblon Degraders

文献类型：期刊论文

作者Deng, Yanan2,5; Yang, Shiling4; Xu, Hesong2,5; Ding, Xiyao2,5; Xu, Ying1,2,5; Ye, Zhengzheng2,5; Chen, Yan2,5; Zhang, Zemin6; Lin, Jin6; Xiong, Huan7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-05-07
卷号68期号:10页码:10111-10127
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00065
英文摘要Cereblon (CRBN)-based protein degradation, via molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs), is a promising cancer treatment strategy in targeted protein degradation (TPD). However, novel degraders discovery remains limited due to the lack of robust, high-throughput screening (HTS) methods for processing pools of purified compounds or complex chemical synthesis mixtures. Here, we introduce an innovative HTS strategy that employs a highly sensitive, fluorescence-coupled ubiquitination assay to identify CRBN-based degraders. This approach tracks ubiquitinated target proteins via gel-based analyses, and thereby progressively narrows down the list of potential degrader molecules from large-scale compound libraries or chemical reaction mixtures. Using this strategy, we identified LL-BPTF-8, a promising lead compound of PROTAC degrader with high potency and selectivity that targets the bromodomain PHD finger transcription factor (BPTF). Overall, our method offers a low-cost, rapid, and versatile platform for the HTS of protein degrader candidates, significantly streamlining the discovery of novel degraders.
WOS关键词PROTEIN ; LIGASE ; DEGRADATION ; DISCOVERY ; MODULATOR ; COMPLEX ; DRUGS
资助项目National Natural Science Foundation of China[2022YFC2804800] ; National Natural Science Foundation of China[2023YFD1800102] ; National Natural Science Foundation of China[2022YFC3400500] ; National Key Research and Development Program of China[82473951] ; National Key Research and Development Program of China[22377013] ; National Key Research and Development Program of China[82473893] ; National Key Research and Development Program of China[81821005] ; National Key Research and Development Program of China[92253303] ; National Key Research and Development Program of China[U23A20108] ; National Key Research and Development Program of China[82304301] ; National Natural Science Foundation of China[GZNL2023A02012] ; Department of Science and Technology of Guangdong Province[LY23H190002] ; Zhejiang Provincial Natural Science Foundation of China[2023HIAS-Y023] ; Hangzhou Institute for Advanced Study[BX20230394] ; Hangzhou Institute for Advanced Study[2023M733628] ; Hangzhou Institute for Advanced Study[2023M733631] ; China Postdoctoral Science Foundation[2023762] ; Shanghai Postdoctoral Excellence Program
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001483258400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317593]  
专题新药研究国家重点实验室
通讯作者Chen, Shijie; Lin, Hua; Li, Zhihai
作者单位1.East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Guizhou Med Univ, Sch Pharm, State Key Lab Funct & Applicat Med Plants, Guiyang 550004, Peoples R China
4.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Key Lab Microbial Pathogenesis & Intervent Fujian, Fuzhou 350117, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Fujian Med Univ, Sch Pharm, Fuzhou 350122, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
推荐引用方式
GB/T 7714		 Deng, Yanan,Yang, Shiling,Xu, Hesong,et al. Fluorescence-Coupled Ubiquitination Assay as a High-Throughput Screening Strategy for Novel Cereblon Degraders[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(10):10111-10127.
APA Deng, Yanan.,Yang, Shiling.,Xu, Hesong.,Ding, Xiyao.,Xu, Ying.,...&Li, Zhihai.(2025).Fluorescence-Coupled Ubiquitination Assay as a High-Throughput Screening Strategy for Novel Cereblon Degraders.JOURNAL OF MEDICINAL CHEMISTRY,68(10),10111-10127.
MLA Deng, Yanan,et al."Fluorescence-Coupled Ubiquitination Assay as a High-Throughput Screening Strategy for Novel Cereblon Degraders".JOURNAL OF MEDICINAL CHEMISTRY 68.10(2025):10111-10127.

入库方式： OAI收割

来源：上海药物研究所

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