Scientists at Dana-Farber Cancer Institute have built a systematic way to discover “molecular glues” — drugs that trick the cell into destroying disease-causing proteins, including ones long considered impossible to target.
A molecular glue degrader works by grabbing an E3 ligase (part of the cell’s protein-disposal machinery) and redirecting it to tag a target protein for destruction through the ubiquitin-proteasome system. That is powerful because many important cancer proteins — such as transcription factors — have no pocket for a traditional inhibitor to bind; degrading them sidesteps that problem entirely.
How the platform works
The team, led by Harvard’s Eric Fischer, fixes E3 ligases to magnetic beads, bathes them in cellular extract and libraries of drug compounds, then uses mass spectrometry to spot which proteins are drawn to a drug-bound ligase. Published in Nature in August 2026, the approach surfaced new degraders — including the first “metabolically activated” molecular glue that switches on under oxidative stress — and degraded cancer targets such as SMARCA2, WEE1 and CDK7.
Why it matters
Molecular glues are a hot frontier in drug development (the blood-cancer drug lenalidomide turned out to be one). “This systematic approach…opens up the possibility for expanding the number of proteins that can be targeted for degradation as a treatment for cancer,” the researchers said. The work is preclinical, but it turns a serendipitous discovery process into a repeatable search.