Nature study identifies molecular glue degrader activated by glutathionylation
This digest was compiled by AI from multiple sources — links to the originals are below.
Researchers report in Nature the discovery of M12, a molecular glue that reprograms the E3 ligase DCAF11 to degrade the protein DDX18. The compound functions as a prodrug, activated by glutathione S-transferase-mediated glutathionylation, enabling targeted degradation of a range of proteins.
Platform and Hit Identification
The study presents an unbiased platform for systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, researchers identified M12 as a compound that reprograms the E3 ligase DCAF11. M12 induces degradation of DDX18, a target not previously linked to DCAF11. The approach mirrors earlier successes with CRBN-based molecular glues such as thalidomide and lenalidomide.
Mechanism of Action
M12 functions as a prodrug that requires activation by glutathione S-transferase enzymes. The glutathione moiety binds to a conserved glutathione-binding site on DCAF11, while the exposed M12 fragment recruits the neo-substrate DDX18. This glutathionylation-dependent mechanism is distinct from the direct binding seen with CRBN-modulating drugs. The study shows DCAF11's evolutionary conservation of the glutathione pocket enables selective degradation.
1 source
Time · lag behind first