Attacking cancer cells from the inside out

Researchers from the University of Toronto (U of T) are harnessing the power of proteins to stop cancer cells in their tracks.

“Proteins are the workhorses of the cell,” said Walid A. Houry, professor of biochemistry at U of T. “They define the cell and allow it to divide or migrate if needed.”

The team is especially interested in proteases, enzymes that chew up old or misfolded proteins and act as cellular quality control. Houry and his colleagues used the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan to identify key compounds affecting these quality control mechanisms that cause cell dysfunction and, ultimately, cell death. Their research paper was recently published in Structure.

“Let’s say you have a small puppy and when you leave it in the room, it starts chewing your sofa, your carpet; it’s just hyper and eating everything up,” Houry said. The compounds cause the proteases to act like the puppy, “and the cell cannot handle this type of disruption to its machinery.”

By targeting the cell’s self-destruct button, Houry’s team, including collaborators at Madera Therapeutics, is designing a new approach to cancer therapy. Synchrotron techniques allowed the researchers to visualize the interaction between their compounds and the proteases.

Houry said hard-to-treat cancers like glioblastomas and certain types of breast cancers are good candidates for this new approach.

“Instead of inhibiting a protease, we are hyperactivating the protease, and that is unique.”

The CLS is crucial to the team’s work.

“Synchrotron technology is extremely important for us and our structure-based drug design,” he said. “We want to know why the protein is going wild when we add our compound.”

The next step of the study is to push the limits of the compounds. Houry also hopes to use them as tools to help visualize the inner workings of the cell.

“If you can play these games with the compounds, that would be really exciting. All of this would be guided by the structures we see at the CLS.”

Mabanglo, Mark F., Keith S. Wong, Marim M. Barghash, Elisa Leung, Stephanie HW Chuang, Afshan Ardalan, Emily M. Majaesic et al. "Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome." Structure 31, no. 2 (2023): 185-200. DOI:https://doi.org/10.1016/j.str.2022.12.002 

Photos: Synchrotron | CMCF beamline | Houry and research team

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