Targeting difficult proteins

Proteins regulate many of the body’s cellular functions, from immune responses to cell division. When proteins become overactive or fail to function properly, they can contribute to disease.

Scientists from the University of British Columbia discovered a new method for designing drugs that bind more strongly to these proteins and block their disease-causing activity. Their research centered on treating a cancer protein that feeds the growth of most prostate cancers and showed that proteins previously believed to be undruggable, such as the prostate cancer protein, could be targeted by drugs.

Using molecular glue to target proteins

University of Toronto researcher Dr. Chetan Chana says many disease-driving proteins are difficult to target because they lack obvious drug-binding pockets or acquire mutations.

A molecular glue binds two proteins together and marks one for destruction.

“Molecular glues are difficult to rationally design and have been discovered serendipitously to date,” said Chana. “Thus, it’s been difficult to rationally design a molecule that can be used to destroy proteins, let alone tune the activity of a protein and this makes them resistant to current treatments.”

Chana’s research team discovered a molecular glue, CLEO4-88, that can deactivate proteins rather than destroy them. This discovery could expand how scientists develop future treatments for disease.

“CLEO4-88 functions differently by binding to only one protein and causing a conformational change that allows it to bind to a second protein,” Chana added.

Using high-powered X-rays at the Canadian Light Source, the researchers observed that the molecular glue reduced the activity of ACAA1, a protein involved in how cells process fats.

“Many proteins perform multiple functions inside cells, meaning completely destroying them could interfere with healthy biological processes and create unwanted side effects,” said Chana. “Selectively slowing or dampening harmful protein activity may provide a more balanced therapeutic approach in some diseases.”

Potential future applications could help target proteins that conventional drugs still struggle to reach, including proteins linked to cancers and metabolic disorders.

The research was conducted at the Canadian Light Source, a national research facility at the University of Saskatchewan, on Treaty 6 Territory and the Homeland of the Métis. The findings were published in the journal Nature Chemical Biology.