DCAF11-dependent molecular glue degrader activated by glutathionylation.

M12 activates the E3 ligase DCAF11 via glutathionylation to promote targeted protein degradation, but specific outcomes are not detailed.

Summary and findings

This study investigates a molecular glue, M12, that activates the E3 ligase DCAF11 through glutathionylation to degrade DDX18. The findings suggest that this mechanism can facilitate the targeted degradation of various proteins. No specific numeric outcomes or treatment effects were reported in the abstract.

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.

Limitations

Not reported in abstract.

Elsewhere in the Glutathione (GSH) corpus