Hijacking cell’s natural machinery to help treat diseases

Proteins do most of the work in our body’s cells. But when a protein is too active or does not function properly, it can lead to disease or other health problems.

Researchers from the University of Toronto have discovered a molecule, CLEO4-88, that acts as a ‘molecular glue,’ binding together two proteins to inactivate one of them. The finding – enabled by the Canadian Light Source (CLS) at the University of Saskatchewan – points to the possibility of one day treating disease by controlling the activity of harmful proteins.

Molecular glues typically stick together two proteins that would not normally interact, marking one of them for destruction. In this study, researcher Chetan Chana and colleagues discovered that instead marking a protein for destruction, CLEO4-88 inactivated it. The team's findings are published in the journal Nature Chemical Biology.

The high-powered X-rays at the CLS enabled the researchers to see that CLEO4-88 stuck two proteins together and slowed down the activity of one of them (ACAA1). While ACAA1 – which is involved in breaking down fats inside cells – was not destroyed, its activity was reduced. This mechanism could potentially be leveraged to control some triple negative breast cancers, where ACAA1 activity has been shown to be elevated.

“This is exciting because molecular glues usually dispose of proteins, but this shows they can also inactivate them,” she said. “There are many examples of diseases caused by overactive proteins.”

The work is important as a proof of concept that expands the field of molecular glues beyond just protein disposal, says Chana. It shows they could also be used to modulate protein activity to control disease. Scientists may be able to develop new medicines that control harmful proteins more precisely, including those involved in cancers and metabolic diseases.

“We might be able to find other molecules that glue to other proteins with a therapeutic benefit,” she says.

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Chana, Chetan K., Ines Ben Makhlouf, Jaeyoun Kim, April JY Yu, Nathalie Moatti, Stephen Orlicky, Cassandra J. Wong et al. "The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4." Nature Chemical Biology (2026): 1-10. https://doi.org/10.1038/s41589-026-02183-4

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