Protein droplets reveal new ways to inhibit transcription factors in prostate cancer
An international team of researchers, led by the Institute for Research in Biomedicine (IRB Barcelona), based in the Barcelona Science Park, has discovered a potential way to target the androgen receptor—the most prominent oncogenic transcription factor in prostate cancer—based on its propensity to form droplets, also known as condensates. The findings, described in Nature Structural & Molecular Biology, laid the groundwork for the foundation of Nuage Therapeutics, a spinoff of IRB Barcelona and ICREA, in September 2021 in the Park. The potential of its science led to a €12M Seed financing round in June 2023.
Many of the most potent human oncoproteins belong to a class of proteins called transcription factors, but designing small molecule drugs that target these is a major challenge. Transcription factors play essential roles in turning the genetic information encoded in genes in all cells and organisms into proteins.
These regulatory proteins bind DNA, turn genes on or off, and regulate the rate at which DNA is transcribed into mRNA, which is needed for protein synthesis. Given the central role of transcription factors in transcriptional control, many diseases can be traced back to the dysregulation of these factors. Inhibiting the activity of these transcription factors, especially in cancer, offers therapeutic potential; however, many have a trick up their sleeve. Their activation domains are intrinsically disordered, meaning that the chains of amino acids that make up the domain lack a clear 3D structure, thus making it virtually impossible to design drugs that bind to these sites.
A research team led by researchers at IRB Barcelona Dr. Xavier Salvatella (ICREA research professor) and Dr. Antoni Riera (Professor at the University of Barcelona); Dr. Denes Hnisz, at the Max Planck Institute for Molecular Genetics; and Dr. Marianne D. Sadar, at BC Cancer (University of British Columbia, Canada), has studied the tendency of intrinsically disordered proteins to form so-called biomolecular condensates. They have found that the mechanisms involved in condensation could be exploited to inhibit androgen receptor activity in prostate cancer.
“The rationale we have followed to optimise an androgen receptor inhibitor could be exploited to inhibit other transcription factors, thus opening up new opportunities to address unmet medical needs,” says Dr. Salvatella.
» For further information: IRB Barcelona website [+]
» Reference article: Basu, S., Martínez-Cristóbal, P., Frigolé-Vivas, M. et al. Rational optimization of a transcription factor activation domain inhibitor. Nat Struct Mol Biol (2023). DOI: 10.1038/s41594-023-01159-5