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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月10日

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  • Yankai Chu,
  • Shishuang Chen,
  • Mingyang Yang,
  • Yin Chen,
  • Huiling Fang,
  • Pinyu Huang,
  • Yueru Xie,
  • Chi Sun,
  • Yun Chen,
  • Baoding Zhang,
  • Li Li,
  • Hongchen Mu,
  • Ding Song,
  • Wentao Cheng,
  • Chao Wang,
  • Wei Jiang,
  • Xiaolan Xu,
  • Zhengjin He,
  • Shuo Chen,
  • Mingxian Liu,
  • Jingchuan Ma,
  • Man Yang,
  • Jiaqi Cao,
  • Jing Gao,
  • Jiali Shen,
  • Lulu Zhang,
  • Yu Bai,
  • Zheyi Liu,
  • Jingyao Chen,
  • Siqi Dai,
  • Yi Arial Zeng,
  • Yun Zhao,
  • Hu Zhou,
  • Chong Chen,
  • Huanwei Ru,
  • Li Tan,
  • Ximin Chi,
  • Fangjun Wang,
  • Daming Gao,
  • Moubin Lin,
  • Xianming Deng,
  • Hai Jiang

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.