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DCAF11-dependent molecular glue degrader activated by glutathionylation

Nature Bioinformatics AI Hojong Yoon, Franziska Wachter, Katharine A. Barrett, Cyrus Jin, Anna Rodríguez-Pöhnlein, Justine C. Rutter, Ryan J. Lumpkin, Rebecca J. Metivier, Katherine A. Donovan, Kheewoong Baek, Yongying Jiang, Minwoo Lee, Robert W. Kalis, Jianwei Che, Yuan Xiong, Eric S. Fischer, Benjamin L. Ebert 2026-08-05

TL;DR - M12 is a metabolically activated molecular glue that directs diverse proteins to DCAF11 for ubiquitin-mediated degradation. Its glutathione-dependent activation could broaden targeted protein degradation to more substrates.

Glutathionylation activates M12’s degrader activity.
M12 recruits multiple protein substrates to the DCAF11 ubiquitin ligase.
Recruited proteins undergo ubiquitin-mediated degradation.
The mechanism expands the potential scope of molecular-glue therapeutics.

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