A new study led by Dr. Marianne D. Sadar, distinguished scientist at BC Cancer and professor of pathology and laboratory medicine at the UBC faculty of medicine, has been published in Nature Signal Transduction and Targeted Therapy, describing a new approach to targeting proteins long considered “undruggable”. The research outlines an enhanced approach that could lead to new treatments for prostate cancer and other diseases.
Few medications can target intrinsically disordered proteins – molecular shapeshifters that are extremely difficult to drug due to their flexible and ever-changing structure. These proteins play a central role in a wide range of diseases including cancer, neurodegenerative disorders, heart disease and autoimmune conditions – yet only a handful of medications currently exist that can target them.
In the study, researchers at BC Cancer and the University of British Columbia demonstrate a new way to design drugs that bind more strongly to these proteins and block their disease-causing activity. In some cases, the compounds bound up to a million times more tightly than any previously reported.
“This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy,” said principal investigator Dr. Sadar. “The findings could have profound implications for the treatment of cancer and other diseases, providing a roadmap for the development of new treatments.”
Unlike most proteins, which fold into stable three-dimensional shapes, disordered proteins lack fixed binding sites, making them extremely difficult to target with traditional drugs. Dr. Sadar and her team have spent decades studying how to target these proteins, developing the first compound capable of binding to them in 2008 and advancing two such drugs into clinical trials.
The new study focused on the androgen receptor, a disordered protein that fuels the growth of most prostate cancers. Rather than targeting a fixed site, the compounds interact with the protein’s moving region, freezing it in an inactive state and preventing it from turning on genes that drive cancer growth. In animal studies, several compounds slowed prostate cancer growth more effectively than a commonly used prostate cancer treatment.
The researchers now aim to advance the most promising candidates toward clinical trials, with the goal of developing prostate cancer drugs that can be used earlier in treatment and with fewer side-effects. Because disordered proteins are involved in many diseases, they say the approach could have a much broader impact.
“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.
This research was supported by the BC Cancer Foundation, U.S. National Institutes of Health, National Cancer Institute and donations from Country Meadows Senior Men's Golf Charity.
This writeup is a shortened version of a UBC Media Release: Drugging the undruggable: Scientists achieve million-fold leap in targeting elusive cancer proteins