2023-12-04 18:03:16
New Ways to Inhibit Transcription Factors in Aggressive Prostate Cancer
An international research team has uncovered a possible target against the androgen receptor, the most important oncogenic transcription factor in prostate cancer. The team, consisting of researchers from the Max Planck Institute for Molecular Genetics, the Institute for Research in Biomedicine (Barcelona), and the University of British Columbia (Vancouver), made the discovery by identifying a weak point in the receptor hidden in its tendency to form droplets within cells. Their findings also led to the formation of the start-up company Nuage Therapeutics.
Transcription factors play an essential role in all cells and organisms by converting genetic information into proteins. Due to their central role in transcription regulation, many diseases can be traced back to defective or overactivated transcription factors. Inhibiting their activity offers therapeutic potential, but many transcription factors have a trick up their sleeves—activation domains that are intrinsically disordered and don’t have a clear three-dimensional structure, making it difficult to develop drugs that bind to them.
The research team focused on the tendency of intrinsically disordered proteins to form biomolecular condensates, discovering that the mechanisms involved in condensation could be used to inhibit androgen receptor activity in prostate cancer.
Biomolecular condensates are tiny protein clumps that resemble droplets floating on water under a microscope, and the condensates are created through a process called demixing or phase separation. The scientists suspected there might be a connection between the activation of the androgen receptor and its tendency to form droplets. They used NMR spectroscopy to identify several short sections within the activation domain that are crucial for phase separation and as well as the activation of genes by the receptor.
The team improved an experimental inhibitor and tested it in cell and mouse models, finding that the changes increased effectiveness in an aggressive form of prostate cancer, castration-resistant prostate cancer.
Nuage Therapeutics, a biotech company founded by members of the research team, is developing drug screening tests that target intrinsically disordered proteins that undergo biomolecular condensation. The scientific potential of the research led to a seed financing round of twelve million euros in June 2023. These findings hold promise for the development of new and safer drugs to address various diseases associated with transcription factors.]
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