2023-12-04 16:03:16
Protein droplets reveal new ways to inhibit transcription factors in an aggressive form of prostate cancer
Many human cancer genes belong to the group of transcription factors. An international research team from the Max Planck Institute for Molecular Genetics, the Institute for Research in Biomedicine (Barcelona) and the University of British Columbia (Vancouver) has now found a possible target once morest the androgen receptor, the most important oncogenic transcription factor in prostate cancer. The team identified a weak point in the receptor, hidden in its tendency to form droplets within cells. The results also form the basis for the founding of the start-up company Nuage Therapeutics.
Super-resolution (τ-STED) imaging of the androgen receptor in human prostate adenocarcinoma cells.
© MPI for molecular genetics
Super-resolution (τ-STED) imaging of the androgen receptor in human prostate adenocarcinoma cells.
© MPI for molecular genetics
Transcription factors play an essential role in all cells and organisms in converting the genetic information encoded in genes into proteins. Transcription factors bind to DNA, turn genes on or off, and control the rate at which DNA is transcribed into the mRNA necessary for protein synthesis. 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. Their activation domains are intrinsically disordered. The amino acid chains that make up these domains do not have a clear three-dimensional structure. The lack of a stable 3D structure makes it difficult to develop drugs that bind to the activation domains.
The research team now focused on the tendency of intrinsically disordered proteins to form biomolecular condensates. They found that the mechanisms involved in condensation might be used to inhibit androgen receptor activity in prostate cancer. “The logic of optimizing an inhibitor of the androgen receptor might also be applied to the inhibition of other transcription factors, opening up new possibilities to address previously unmet medical needs,” says Xavier Salvatella.
Cellular droplets as a new starting point
Biomolecular condensates are tiny protein clumps that resemble droplets floating on water under a microscope. The condensates are created through a process called demixing or phase separation. Two immiscible liquids separate into two phases, similar to oil and water. “We had previously observed that the androgen receptor forms biomolecular condensates when even tiny amounts of an activating molecule such as testosterone are supplied to the cells,” says Shaon Basu, one of the first authors of the study, who now works as a computational biologist at the Berlin Charité.
The scientists suspected that there might be a connection between the activation of the androgen receptor and its tendency to form droplets. In collaboration with biophysicist Xavier Salvatella, they used NMR spectroscopy to identify several short sections within the activation domain that are crucial for phase separation. It was also shown that the same sections also play a role in the activation of genes by the receptor. “We discovered short sequences in the activation domain that are disordered when the protein is soluble, and surprisingly, these regions seem to form more stable structures when the protein is concentrated in condensates,” explains Denes Hnisz. These structures form temporary targets to which inhibitors can bind when the receptor is present in condensates.
Improved active ingredients for the treatment of prostate cancer
Working with Antoni Riera and Marianne Sadar, the team improved an experimental inhibitor. They then tested in cell and mouse models whether these changes would increase effectiveness in an aggressive form of prostate cancer. “We modified the chemical properties of the active ingredient to match the properties of androgen receptor condensation, which resulted in a tenfold increase in the effectiveness of the molecule in castration-resistant prostate cancer,” says Paula Martínez-Cristobal, also lead author of the study from the Institute for Research in Biomedicine in Barcelona. “This is of great importance because castration-resistant prostate cancer is an extremely aggressive cancer that is resistant to currently used first-line agents,” she adds.
However, further research is necessary before these findings can be used to develop new and safer drugs. The team hopes that the basic mechanisms can also be transferred to other transcription factors, thereby opening up the possibility of using these important molecules specifically once morest many different diseases. “We believe that the idea that there are specific sequences within intrinsically disordered protein domains that adopt a transiently stable structure in condensates is universal and can probably be transferred to other transcription factors,” concludes Denes Hnisz.
Nuage Therapeutics
Nuage Therapeutics, a biotech company founded by Xavier Salvatella, Mateusz Biesaga, Denes Hnisz and Judit Anido, is developing drug screening tests that target intrinsically disordered proteins that undergo biomolecular condensation. The results now published laid the foundation for the founding of the company in September 2021, whose scientific potential led to a seed financing round of twelve million euros in June 2023.
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