Dana-Farber Unveils 7-Ligase Platform, Finds First Metabolically Activated Molecular Glue
Updated
Updated · Medical Daily · Aug 7
Dana-Farber Unveils 7-Ligase Platform, Finds First Metabolically Activated Molecular Glue
3 articles · Updated · Medical Daily · Aug 7
Summary
Nature-published work from Dana-Farber describes a screening platform that systematically searches for molecular glues—small molecules that direct E3 ligases to destroy disease-driving proteins rather than merely block them.
Seven E3 ligases screened with magnetic beads, cellular lysate and mass spectrometry led researchers to DCAF11, DDX18 and a compound called M12, providing a proof-of-principle hit.
Cryo-EM showed M12 works only after glutathionylation inside cells, making it the first reported metabolically activated molecular glue degrader and suggesting activity could be tuned to oxidative-stress conditions more common in tumors.
The activated compound was further adapted to degrade cancer-related targets including SMARCA2, WEE1 and CDK7, though Dana-Farber said more work is needed to identify any drug candidate.
No clinical candidate or patient use has been announced; the advance is an early discovery tool aimed at expanding protein degradation beyond the small fraction of roughly 600 human E3 ligases used so far.