New strategy for targeting cancer-causing protein previously considered “undruggable”

A cancer-causing protein long thought to be resistant to medication could soon be the target of new drugs, thanks to the work of Quebec researchers who used synchrotron light to find and exploit its weak spot.

Dr. Steven LaPlante, a professor at Quebec’s Institut National de la Recherche Scientifique (INRS), and his team studied a type of protein called Ras, “which is highly related to a good percentage of the cancers that are out there,” especially those of the head, neck and urinary tract. Ras proteins act as a molecular “switch,” flipping between active and inactive modes; they play a critical role in cell signaling and growth regulation and are often mutated in cancers. Major pharmaceutical companies have studied Ras for years, trying to develop new medications, says LaPlante, but have only recently begun to make some breakthroughs.

LaPlante, who worked in the a pharmaceutical industry before joining INRS, said he wanted to take a new approach to the problem, “to start everything from scratch, like making a nice cake – you start from scratch and when you do that, you really have control over how to optimize every segment (of the process) and make a really good cake.”

Using the Canadian Light Source (CLS) at the University of Saskatchewan, LaPlante and his team gathered atomic-level, 3D information about the protein; they discovered a “pocket” in it that appears to be an ideal target for molecular drug treatment. But, he added, it is “a cryptic pocket – it’s there sometimes and not there other times,” depending on the state of the protein.

The researchers found that, when the Ras protein is in its mutated, cancer-causing state, “molecules snuggle inside the pocket.” “Using crystallography, we were able to look at the mutant proteins to better understand what their structures are,” says LaPlante. Their work was recently published in the journal ACS Omega.

“We know the shape of the protein, we know the dynamics of the pocket, so we can rationally design compounds or drug seeds that enter and stop the cancer-causing properties,” says LaPlante. “We discovered compounds that attach to the pocket and have crystal 3D structures of the complex.” The next stage of the research is to use the ensemble of information to design more potent compounds that can serve as drug candidates that "plug up the protein and inhibit its ability to produce cancer cells,” he says.

A long-time CLS user, LaPlante appreciates having access to the unique Canadian facility in his quest “to find new ways to discover drugs.”

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França, Tanos CC, Michael Maddalena, Imène Kouidmi, Yann Ayotte, Salim T. Islam, and Steven R. LaPlante. "SI/II Pocket of Ras: An Opportunity for a Once “Undruggable” Target." Acs Omega (2025). https://doi.org/10.1021/acsomega.4c10493

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Greg Basky
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Canadian Light Source
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