Nature study identifies molecular glue degrader activated by glutathionylation
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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.
What's Next
Further work will explore the platform's applicability to other E3 ligases and disease targets. It remains uncertain whether metabolically activated degraders can achieve the specificity and safety needed for clinical translation.
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Nature study identifies molecular glue degrader activated by glutathionylation
