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
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.
University of Chinese Academy of Sciences, Beijing, China.
Nat Biotechnol. 2025 Sep 10. doi: 10.1038/s41587-025-02793-8.
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.
靶向蛋白质降解剂有望成为针对传统上“不可成药”蛋白质的治疗药物。在此，我们开发了一种高通量筛选方法——死亡融合逃逸筛选法（DEFUSE），以鉴定小分子蛋白质降解剂。通过将感兴趣的蛋白质与一种快速作用的可触发死亡蛋白偶联，这种方法将靶蛋白降解转化为细胞存活表型，以表明降解剂的存在。利用这种方法，我们发现了一种小分子（SKPer1），它能触发癌蛋白SKP2的降解，并特异性杀死表达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，作为一种诱导邻近降解剂发挥作用，导致SKP2泛素化和降解。SKPer1在体内表现出显著的肿瘤抑制作用且安全性良好。我们进一步表明，来自SKP2的一段十个氨基酸的序列可作为一种通用的降解标签。
