丹娜-法伯癌症研究所Benjamin L. Ebert小组在研究中取得进展。他们发现了由谷胱甘肽化激活的DCAF11依赖性分子胶降解剂。2026年8月5日，国际知名学术期刊《自然》发表了这一成果。

在这里，该课题组研究人员报告了一个公正和广泛适用的平台，用于系统地发现不同E3连接酶的分子胶。使用基于多重质谱的化学筛选，课题组鉴定了M12，一种分子胶，它重新编程E3连接酶DCAF11以降解DDX18。从机制上讲，M12作为前药通过谷胱甘肽S转移酶介导的谷胱甘肽酰化激活。谷胱甘肽片段与DCAF11上进化保守的谷胱甘肽结合位点结合，暴露的M12片段促进新底物招募。该团队证明这种依赖谷胱甘肽的机制很容易使一系列蛋白质的靶向降解成为可能。总的来说，这些发现表明代谢激活的化合物可以重定向E3连接酶的功能，从而扩大了靶向蛋白质降解和化学诱导接近的范围。

据了解，靶向蛋白质降解是一种强大的药理学策略，它利用泛素蛋白酶体系统来消除疾病相关蛋白质，包括其他不可药物的蛋白质。

附：英文原文

Title: DCAF11-dependent molecular glue degrader activated by glutathionylation

Author: Yoon, Hojong, Wachter, Franziska, Barrett, Katharine A., Jin, Cyrus, Rodrguez-Phnlein, Anna, Rutter, Justine C., Lumpkin, Ryan J., Metivier, Rebecca J., Donovan, Katherine A., Baek, Kheewoong, Jiang, Yongying, Lee, Minwoo, Kalis, Robert W., Che, Jianwei, Xiong, Yuan, Fischer, Eric S., Ebert, Benjamin L.

Issue&Volume: 2026-08-05

Abstract: Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.

DOI: 10.1038/s41586-026-10873-1

Source: https://www.nature.com/articles/s41586-026-10873-1