中国科学院上海生命科学研究院生物化学与细胞生物学研究所姜海团队报道了诱导接近降解物的快速成像筛选鉴定出致癌蛋白SKP2的有效降解物。这一研究成果发表在2025年9月10日出版的国际学术期刊《自然—生物技术》上。

该研究团队开发了一种高通量筛选，DEath FUSion Escaper（化解），以识别小分子蛋白质降解物。通过将感兴趣的蛋白与快速作用的可触发死亡蛋白结合，该方法将目标蛋白降解转化为细胞存活表型，以阐明降解物的存在。通过这种方法，课题组研究人员发现了一个小分子（SKPer1），它可以触发癌蛋白SKP2的降解，并特异性地杀死表达SKP2的癌细胞。从机制上讲，SKPer1通过诱导SKP2与E3连接酶STUB1之间的相互作用，导致SKP2泛素化和降解，从而作为诱导接近降解物。SKPer1在体内表现出明显的肿瘤抑制作用和良好的安全性。课题组进一步证明SKP2的十个氨基酸序列可以作为多功能降解标签。

据悉，靶向蛋白质降解剂作为靶向传统“不可药物”蛋白质的治疗药物具有潜力。

附：英文原文

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

Author: 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

Issue&Volume: 2025-09-10

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.

DOI: 10.1038/s41587-025-02793-8

Source: https://www.nature.com/articles/s41587-025-02793-8