Researchers Find M12 Glue Degrader That Drives DCAF11 to Eliminate DDX18
Updated
Updated · Nature.com · Aug 5
Researchers Find M12 Glue Degrader That Drives DCAF11 to Eliminate DDX18
1 articles · Updated · Nature.com · Aug 5
Summary
M12 emerged from a 5,000-compound screen as a molecular glue that recruits the E3 ligase DCAF11 to degrade the RNA helicase DDX18 through the ubiquitin-proteasome system.
Mechanistic tests showed M12 is a prodrug: glutathione S-transferase adds glutathione to form GSH-M12, the active species that binds a conserved DCAF11 pocket and enables DDX18 recruitment.
A 2.3-angstrom cryo-EM structure and CRISPR knockout screens tied the effect specifically to the CRL4-DCAF11 complex; blocking DCAF11 or proteasome-pathway components prevented DDX18 loss.
The team said the lysate-based multiplexed platform can uncover molecular glues across diverse E3 ligases, addressing a bottleneck in expanding targeted protein degradation beyond a few well-studied ligases.
M12 also served as a DCAF11 warhead in prototype PROTACs that degraded BRD4, SMARCA2, BRD9 and several kinases, suggesting a broader route to drug otherwise hard-to-target proteins.
What hidden toxicities might emerge when healthy cells inadvertently activate these powerful protein-destroying prodrugs?
Could hijacking a cell's own metabolism to activate molecular glues finally unlock therapies for previously undruggable diseases?
How might cancer cells exploit fluctuating glutathione levels to resist this newly discovered metabolically activated molecular glue?
The M12–DCAF11 Breakthrough: Metabolically Activated Molecular Glues Redefine Targeted Protein Degradation and Cancer Selectivity (2024)
Overview
In May 2024, researchers made a breakthrough by developing a high-throughput screening platform that led to the discovery of M12, a molecular glue that links the E3 ligase DCAF11 to the cancer-driving protein DDX18. Unlike traditional glues, M12 acts as a prodrug, requiring activation inside cells by glutathione S-transferase (GST) and glutathione (GSH) through S-glutathionylation. This activation happens rapidly in cancer cells, which have high GST and GSH levels, making M12 highly selective and reducing harm to healthy tissues. The platform also enables the creation of new degraders for other cancer targets, while advanced models and AI help address safety and resistance challenges.