DCAF11-dependent molecular glue degrader activated by glutathionylation

ABSTRACT: Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins. 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 a molecular glue, M12, that reprograms the E3 ligase DCAF11 to degrade DDX18. We found that M12 functions as a prodrug, activated by glutathionylation. The glutathione moiety then directly engages DCAF11, enabling neo-substrate recruitment. We demonstrate that this mechanism readily enables targeted degradation of a range of proteins. Our studies highlight a novel approach to redirect E3 ligase function through an enzyme-activated small molecule, expanding the scope of targeted protein degradation and chemically induced proximity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD067066 | Pride | 2026-06-18

REPOSITORIES: Pride