Drugging the undruggable: Scientists achieve million-fold leap in targeting elusive cancer proteins

New research outlines an enhanced approach that could lead to treatments for prostate cancer and other diseases.

Researchers at UBC and BC Cancer have developed a new way to target proteins long considered “undruggable,” opening the door to new treatments for prostate cancer and other serious diseases.  

Known as intrinsically disordered proteins, these molecular shapeshifters are extremely difficult to target with medication due to their flexible and ever-changing structure. They play a central role in a wide range of diseases—including cancer, neurodegenerative disorders, heart disease and autoimmune conditions.

In a study published today in Nature Signal Transduction and Targeted Therapy, the researchers demonstrate a new approach for designing drugs that bind more strongly to these proteins and block their disease-causing activity. In some cases, the compounds they developed 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. Marianne D. 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.”

Unlike most proteins, which fold into stable three-dimensional shapes, disordered proteins contain flexible regions that change as they interact with molecules inside cells. Because they lack fixed binding sites, they are extremely difficult to target with traditional drugs.

“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.”

A new strategy against prostate cancer

The new study focused on a specific protein, the androgen receptor, which fuels the growth of most prostate cancers.

Rather than fitting into a single fixed spot, the researchers developed compounds that interact with the moving region of the protein, freeze it in an inactive state, and prevent it from turning on genes that drive cancer growth.

“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 departments of chemistry, and earth ocean and atmospheric Sciences. “We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working.”

By systematically modifying the compounds at the molecular level, the researchers identified several promising candidates that effectively shut down the receptor. In animal studies, several compounds slowed prostate cancer growth more effectively than a commonly used prostate cancer treatment.

“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.

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 U.S. National Institutes of Health (NIH)/National Cancer Institute (NCI) and donations from Country Meadows Senior Mens’ Golf Charity and BC Cancer Foundation.