University of British Columbia and BC Cancer researchers have developed a new method for targeting intrinsically disordered proteins, demonstrating unprecedented binding affinity to the androgen receptor, with some candidates outperforming existing prostate cancer treatments in preclinical models.
Researchers at the University of British Columbia and BC Cancer have announced a promising new approach to targeting proteins long considered ’undruggable’. The hope is that this could potentially lead to more effective treatments for prostate cancer and other serious diseases.
These proteins, known as intrinsically disordered proteins, are notoriously difficult to treat with conventional drugs. Unlike typical proteins, they do not maintain a stable three-dimensional structure, instead shifting constantly as they interact with other molecules in the body. Their unpredictable nature has made them a challenge for scientists, despite their involvement in a wide range of illnesses including cancer, neurodegenerative disorders, heart disease and autoimmune conditions.
In this study, the team demonstrated a novel method for designing compounds that can bind strongly to these elusive proteins and block their harmful activity. In some cases, the newly developed compounds showed binding strengths up to a million times greater than previously reported.
“This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy,” said Principal Investigator Dr Marianne Sadar, Professor of Pathology and Laboratory Medicine at the UBC Faculty of Medicine and Distinguished Scientist at BC Cancer. “The findings could have profound implications for the treatment of cancer and other diseases, providing a roadmap for the development of new treatments.”
A long-standing challenge in drug discovery
Traditional drug development relies on designing molecules that fit precisely into fixed structures on proteins. However, intrinsically disordered proteins do not conform to this model.
Traditional drug development relies on designing molecules that fit precisely into fixed structures on proteins
“Most drug discovery is like designing a key for a very specific lock,” said Dr Sadar. “But disordered proteins don’t behave like locks at all, they’re more like moving strands of spaghetti.”
Dr Sadar and her team have been working on this problem for decades. In 2008, they created the first compound capable of binding to such proteins and have since progressed two drugs into clinical trials. Despite this progress, achieving strong and reliable binding has been difficult.
A new strategy against prostate cancer
The latest research focused on the androgen receptor, a protein that drives the growth of most prostate cancers. Instead of targeting a fixed binding site, the team developed compounds that attach to the protein’s flexible regions, effectively locking it into an inactive state. This prevents the receptor from activating genes that promote tumour growth.
“It’s a major achievement. Our target drugs had binding affinity a million times greater than existing drugs targeting these regions,” said Dr Natalie Strynadka, Professor of Biochemistry and Molecular Biology at the UBC Faculty of Medicine.
Through careful molecular modifications, the researchers identified several compounds that successfully inhibited the receptor. In animal studies, some of these compounds slowed tumour growth more effectively than a commonly used prostate cancer treatment.
“What surprised us was how effectively these molecules could attach to a protein that doesn’t have a fixed structure,” said Dr Raymond Andersen, Professor in UBC’s Department of Chemistry. “We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working.”
Toward clinical trials
The team is now working to progress the most promising candidates into clinical trials, with the aim of developing treatments that can be used earlier and with fewer side effects. Because intrinsically disordered proteins are implicated in many diseases, the researchers believe their approach could be useful for treating other conditions.
The team is now working to progress the most promising candidates into clinical trials
“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 for drug discovery,” said Dr Sadar.
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