In a new study published in Nature Signal Transduction and Targeted Therapy titled, “Drugging the intrinsically disordered transactivation domain of androgen receptor,” researchers from the University of British Columbia and BC Cancer present a new approach for designing drugs that bind more strongly to intrinsically disordered proteins. These proteins play a central role in a wide range of diseases, including cancer, neurodegenerative disorders, heart disease and autoimmune conditions, and are extremely difficult to target due to their flexible nature.
Transactivation domains (TADs) of transcription factors are enriched in intrinsically disordered regions (IDRs) that lack a stable three-dimensional structure. The plasticity of an IDR permits dynamic conformations that regulate cellular and biological functions.
The new study developed inhibitors that bound to the TADs of the androgen receptor, a therapeutic target for prostate cancer. While therapeutic interventions often target its folded ligand-binding domain (LBD), resistance ultimately develops due to reactivation of androgen receptor signaling.
Inhibitors stabilized the protein in the inactive state to prevent the activation of genes that drive cancer growth. In animal studies, several compounds slowed prostate cancer growth more effectively than a commonly used prostate cancer treatment. Notably, several antigen receptor TAD inhibitors displayed strong binding affinities higher than, or were comparable to the LBD-inhibitor enzalutamide, with dissociation constants in the picomolar to low-nanomolar range
“Most drug discovery is like designing a key for a very specific lock,” said Marianne Sadar, PhD, professor of pathology and laboratory medicine at the UBC faculty of medicine, distinguished scientist at BC Cancer, and co-corresponding author of the study. “But disordered proteins don’t behave like locks at all, they’re more like moving strands of spaghetti.”
“This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy,” she continued. “The findings could have profound implications for the treatment of cancer and other diseases, providing a roadmap for the development of new treatments.”
“What surprised us was how effectively these molecules could attach to a protein that doesn’t have a fixed structure,” said Raymond Andersen, PhD, professor in UBC’s department of chemistry and co-corresponding author of the study. “We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working.”
The researchers now aim to advance the most promising candidates toward clinical trials, with the goal of developing prostate cancer drugs for early intervention and with fewer side-effects.
“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 Sadar.
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