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

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

  • Nat Biotechnol. 2025 Sep 10. doi: 10.1038/s41587-025-02793-8.
Yankai Chu # 1 2,  Shishuang Chen # 1 2,  Mingyang Yang # 3,  Yin Chen # 1 2,  Huiling Fang # 1 2,  Pinyu Huang 1 2,  Yueru Xie 1,  Chi Sun 3,  Yun Chen 3,  Baoding Zhang 3,  Li Li 3,  Hongchen Mu 3,  Ding Song 3,  Wentao Cheng 3,  Chao Wang 1,  Wei Jiang 4,  Xiaolan Xu 4,  Zhengjin He 1,  Shuo Chen 4,  Mingxian Liu 1,  Jingchuan Ma 1,  Man Yang 1 2,  Jiaqi Cao 1 2,  Jing Gao 2 5 6,  Jiali Shen 2 7,  Lulu Zhang 8,  Yu Bai 9,  Zheyi Liu 9,  Jingyao Chen 10,  Siqi Dai 11,  Yi Arial Zeng 4 12,  Yun Zhao 4 13,  Hu Zhou 5 6,  Chong Chen 11,  Huanwei Ru 14,  Li Tan 7,  Ximin Chi 3,  Fangjun Wang 9,  Daming Gao 8,  Moubin Lin 15,  Xianming Deng 16,  Hai Jiang 17 18
Affiliations

Affiliations

  • 1 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 4 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 5 Institute of Materia Media, Chinese Academy of Sciences, Shanghai, China.
  • 6 Shanghai Institute of Materia Medica-University of Ottawa Joint Research Center in Systems and Personalized Pharmacology, Shanghai, China.
  • 7 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 8 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 9 CAS Key Laboratory of Separation Sciences for Analytical Chemistry, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 10 Laboratory of Precision Therapeutics, West China Hospital, Sichuan University, Chengdu, China.
  • 11 Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
  • 12 New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 13 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 14 Defand Therapeutics, Hangzhou, China.
  • 15 Department of General Surgery, Yangpu Hospital, Institute of Gastrointestinal Surgery and Translational Medicine, Tongji University School of Medicine, Shanghai, China.
  • 16 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. xmdeng@xmu.edu.cn.
  • 17 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. hai@sibcb.ac.cn.
  • 18 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. hai@sibcb.ac.cn.
  • # Contributed equally.
PMID: 40931108 DOI: 10.1038/s41587-025-02793-8
Abstract

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.

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