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A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2

文献类型：期刊论文

作者Chu, Yankai15,16; Chen, Shishuang15,16; Yang, Mingyang14; Chen, Yin15,16; Fang, Huiling15,16; Huang, Pinyu15,16; Xie, Yueru16; Sun, Chi14; Chen, Yun14; Zhang, Baoding14
刊名NATURE BIOTECHNOLOGY
出版日期2025-09-10
页码30
ISSN号1087-0156
DOI10.1038/s41587-025-02793-8
通讯作者Deng, Xianming(xmdeng@xmu.edu.cn) ; Jiang, Hai(hai@sibcb.ac.cn)
英文摘要Targeted protein degraders hold potential as therapeutic agents to target conventionally 'undruggable' proteins. Here, we develop a high-throughput screen, DEath FUSion Escaper (DEFUSE), to identify small-molecule protein degraders. By conjugating the protein of interest to a fast-acting triggerable death protein, this approach translates target protein degradation into a cell survival phenotype to illustrate the presence of degraders. Using this method, we discovered a small molecule (SKPer1) that triggers degradation of the oncoprotein SKP2 and specifically kills SKP2-expressing cancer cells. Mechanistically, SKPer1 acts as an induced-proximity degrader by inducing interaction between SKP2 and an E3 ligase, STUB1, resulting in SKP2 ubiquitination and degradation. SKPer1 exhibits substantial tumour suppression with good safety profiles in vivo. We further show that a sequence of ten amino acids from SKP2 can serve as a versatile degradation tag.
WOS关键词TARGETED PROTEIN-DEGRADATION ; DOWN-REGULATION ; P27(KIP1) ; TRANSCRIPTION ; PROGRESSION ; CEREBLON ; PATHWAY ; CELLS
资助项目National Key RD Program[2020YFA0509001] ; National Key RD Program[2024YFA1306204] ; National Key RD Program[2022YFC2804100] ; Strategic Priority Research Program of the Chinese Academy of Science[XDB1260201] ; Strategic Priority Research Program of the Chinese Academy of Science[XDB0570000] ; National Natural Science Foundation of China[22025702] ; National Natural Science Foundation of China[82021003] ; National Natural Science Foundation of China[22494692] ; National Natural Science Foundation of China[92253303] ; National Natural Science Foundation of China[82473183] ; National Natural Science Foundation of China[81972600] ; National Natural Science Foundation of China[82073874] ; Fundamental Research Funds for the Central Universities of China[20720220050] ; State Bureau of Foreign Experts ; Ministry of Education of China[BP2018017] ; New Cornerstone Science Foundation[NCI202254] ; CAS Project for Young Scientists in Basic Research[YSBR-014]
WOS研究方向Biotechnology & Applied Microbiology
语种英语
WOS记录号WOS:001567692100001
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/321432]  
专题中国科学院上海药物研究所
通讯作者Deng, Xianming; Jiang, Hai
作者单位1.Tongji Univ, Yangpu Hosp, Sch Med, Dept Gen Surg,Inst Gastrointestinal Surg & Transla, Shanghai, Peoples R China
2.Defand Therapeut, Hangzhou, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, New Cornerstone Sci Lab,Key Lab Multi Cell Syst, Shanghai, Peoples R China
5.Sichuan Univ, West China Hosp, Canc Ctr, Chengdu, Peoples R China
6.Sichuan Univ, West China Hosp, Dept Thorac Oncol, State Key Lab Biotherapy, Chengdu, Peoples R China
7.Sichuan Univ, West China Hosp, Lab Precis Therapeut, Chengdu, Peoples R China
8.Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, State Key Lab Mol React Dynam, Dalian, Peoples R China
9.Chinese Acad Sci, Key Lab Multicell Syst, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Shanghai, Peoples R China
10.Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Chu, Yankai,Chen, Shishuang,Yang, Mingyang,et al. A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2[J]. NATURE BIOTECHNOLOGY,2025:30.
APA Chu, Yankai.,Chen, Shishuang.,Yang, Mingyang.,Chen, Yin.,Fang, Huiling.,...&Jiang, Hai.(2025).A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2.NATURE BIOTECHNOLOGY,30.
MLA Chu, Yankai,et al."A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2".NATURE BIOTECHNOLOGY (2025):30.

入库方式： OAI收割

来源：上海药物研究所

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