DCAF11-dependent molecular glue degrader activated by glutathionylation
- 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
Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins 1 . 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.