Dana-Farber researchers develop systematic molecular glue discovery platform, report first activated degrader
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Researchers at Dana-Farber Cancer Institute have built a systematic platform for discovering molecular glue degraders that redirect E3 ligases to tag disease-related proteins for disposal, as reported Aug. 6 in Nature. The platform uncovered the first molecular glue degrader that is metabolically activated, opening the possibility of context-dependent protein degradation for cancer treatment.
Platform Design
The team’s screen fixes a subset of E3 ligases to magnetic beads, exposes them to cellular lysate and a drug library, then uses mass spectrometry to identify proteins that gain affinity. Co-first author Hojong Yoon, now at MD Anderson Cancer Center, devised the initial workflow. A drug hit occurs when a compound binds an E3 ligase and increases its attraction for a cellular protein, suggesting the pair would be tagged for degradation inside a cell.
Metabolically Activated Degrader
The platform identified a molecular glue that becomes active only when metabolized, marking the first context-dependent degrader. This degrader binds an E3 ligase and tags a target protein for destruction only under conditions of oxidative stress, which is common in cancer cells. The finding, reported in Nature, indicates that molecular glues can be tuned to specific tissue environments, potentially reducing off-target effects.
Broadening the Degrader Toolbox
In 2014, Dana-Farber CEO Benjamin Ebert showed that the myeloma drug lenalidomide works as a molecular glue degrader of a transcription factor, opening a new class of targets. Since then, several degraders have entered clinical trials, but they exploit only a handful of the 600 E3 ligases in the human genome. Co-senior author Eric Fischer described the platform as a scalable approach to expand molecular glue applications for cancer and other diseases.
What's Next
The team plans to apply the platform to other E3 ligases and disease targets, aiming to build a broader library of drug candidates. It remains unclear how many such metabolically activated degraders exist or whether they will translate into effective therapies, but the method could reshape the design of precision cancer drugs.
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Dana-Farber researchers develop systematic molecular glue discovery platform, report first activated degrader
