Molecular glues, tiny molecules that connect one protein to another, are promising targets for pharmaceutical research. By linking a disease-related protein to one that triggers a cell’s demolition and recycling pathways, pharmaceutical researchers have been able to develop novel therapies for otherwise drug-resistant diseases.
It was thought, however, that this approach to drug development was limited to only those proteins that had a specific surface feature called a beta-hairpin loop motif.
Expanding on this once-narrow discovery space, new research published in the journal Science has uncovered a vastly wider array of protein surface features capable of binding with a molecular glue degrader (a pharmaceutical version of a molecular glue molecule). These results may open new pathways for treating diseases by targeting proteins previously thought to be ‘untouchable’ to drug therapies.
Molecular glue degraders function by first latching onto a protein called Cereblon, which is part of the cell’s protein-recycling process. The molecular glue degrader then induces small changes to the surface of the Cereblon protein, essentially creating a docking site for otherwise inaccessible target protein. Once connected, Cereblon tags the protein with a molecule called E3 ubiquitin ligase, which cues the cell to dismantle the protein.
The researchers began by computationally searching the human proteome (protein’s version of the genome) for features that might be a good-enough match for a prototypical molecular glue receptor. This initially uncovered 1633 human proteins that, because of a loop-like motif on their surfaces, might be compatible with Cereblon.
This mining approach not only identified beta-hairpin loops in human proteome but also uncovered helical loops, which are a structurally distinct but sufficient compatible recognition motif.
Among their findings, the research identified VAV1, a protein previously inaccessible to drugs that has broad therapeutic potential in autoimmune and chronic inflammatory disease.
The researchers write: “Our systematic exploration of the CRBN [Cereblon] target space unveils an extraordinary plasticity of CRBN, redefines rules for target engagement, and provides opportunities for target space expansion within and beyond the beta-hairpin G-loop paradigm.”
It bears noting that the drug thalidomide was later discovered to act as a molecular glue degrader. Though pulled from the market in the 1960s due to its devastating side effects when taken during pregnancy, it has since seen a resurgence for its ability to treat a type of cancer and is an effective therapy for inflammation in patients with Hansen’s disease.
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More information:
Georg Petzold et al, Mining the CRBN target space redefines rules for molecular glue–induced neosubstrate recognition, Science (2025). DOI: 10.1126/science.adt6736
Marcus D. Hartmann, Expanding the reach of molecular glue degraders, Science (2025). DOI: 10.1126/science.ady4446
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Data mining uncovers treasure-trove of previously ‘untouchable’ proteins for drug development (2025, July 12)
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