Nature biotechnology · 2025
A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2.
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Chu Yankai, Chen Shishuang, Yang Mingyang, Chen Yin, Fang Huiling, Huang Pinyu, Xie Yueru, Sun Chi, Chen Yun, Zhang Baoding, Li Li, Mu Hongchen, Song Ding, Cheng Wentao, Wang Chao, Jiang Wei, Xu Xiaolan, He Zhengjin, Chen Shuo, Liu Mingxian, Ma Jingchuan, Yang Man, Cao Jiaqi, Gao Jing, Shen Jiali, Zhang Lulu, Bai Yu, Liu Zheyi, Chen Jingyao, Dai Siqi, Zeng Yi Arial, Zhao Yun, Zhou Hu, Chen Chong, Ru Huanwei, Tan Li, Chi Ximin, Wang Fangjun, Gao Daming, Lin Moubin, Deng Xianming, Jiang Hai
Аннотация
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.