UBC Scientists Crack Code on "Undruggable" Cancer Proteins

Scientists just unlocked a door that doctors have been pushing against for decades, and what's behind it could change how we treat cancer forever.

Researchers at the University of British Columbia and BC Cancer have cracked the code on "undruggable" proteins, those slippery molecules that fuel most prostate cancers and play central roles in diseases from Alzheimer's to heart disease. These proteins, called intrinsically disordered proteins, have stumped scientists for years because they constantly change shape like molecular shapeshifters.

Dr. Marianne D. Sadar, the lead researcher, explains the challenge simply: "Most drug discovery is like designing a key for a very specific lock. But disordered proteins don't behave like locks at all. They're more like moving strands of spaghetti."

Her team spent decades figuring out how to grab hold of that spaghetti. In their study published in Nature Signal Transduction and Targeted Therapy, they revealed compounds that bind to these shape-shifting proteins up to a million times more tightly than anything previously created.

The breakthrough focuses on the androgen receptor, the protein that drives most prostate cancer growth. Instead of trying to find a fixed spot to attach to, the researchers designed drugs that interact with the moving parts of the protein, freeze it in place, and stop it from activating cancer-causing genes.

In animal studies, several of these new compounds slowed prostate cancer growth more effectively than current standard treatments. Even more promising, they worked in situations where existing prostate cancer drugs had stopped working.

"What surprised us was how effectively these molecules could attach to a protein that doesn't have a fixed structure," said Dr. Raymond Andersen, a chemistry professor on the team. "We were able to shut down the androgen receptor even when traditional drugs failed."

The Ripple Effect spreads far beyond prostate cancer. Because these disordered proteins are involved in neurodegenerative disorders, heart disease, and autoimmune conditions, this approach could unlock treatments for dozens of diseases that have frustrated doctors for generations.

The team is now working to advance the most promising compounds toward clinical trials, aiming to develop prostate cancer drugs that can be used earlier in treatment with fewer side effects.

Dr. Sadar and her team already made history in 2008 by developing the first compound capable of binding to these proteins, and they've since advanced two drugs into clinical trials, both world-first achievements. This latest breakthrough takes that progress to an entirely new level.

"This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy," Dr. Sadar said. "If the approach continues to prove successful, it could dramatically expand the number of proteins that scientists can target with medicines, turning what was once considered a dead end into a promising new frontier."