Transcription factors are crucial for converting genetic information into proteins in all organisms and cells. These regulatory proteins control gene expression by binding to DNA and regulating the transcription process. Dysregulation of transcription factors can lead to various diseases, making them attractive targets for therapeutic intervention. However, inhibiting the activity of transcription factors, particularly in cancer, is challenging due to the unique structure of their activation domains.
Activation domains of transcription factors are intrinsically disordered, meaning they lack a stable three-dimensional structure. This lack of structural stability makes it difficult to design drugs that can effectively bind to these domains and inhibit their activity. A team of researchers led by Drs. Xavier Salvatella and Antoni Riera at IRB Barcelona, ICREA, and the University of Barcelona, along with Denes Hnisz at the Max Planck Institute for Molecular Genetics and Marianne D. Sadar at BC Cancer, focused on a potential solution to this problem.
The research team investigated the formation of biomolecular condensates, which are protein droplets that resemble blobs floating on water. These condensates are formed through liquid-liquid phase separation, a process similar to oil droplets merging in water. The team observed that the androgen receptor, a transcription factor involved in prostate cancer, forms biomolecular condensates when activated by molecules such as testosterone.
The researchers hypothesized that there might be a connection between the activation of the androgen receptor and its ability to form these droplets. Using nuclear magnetic resonance techniques, they identified specific regions within the intrinsically disordered activation domain that are essential for phase separation. Interestingly, these regions were also crucial for the gene-activating function of the receptor.
The team discovered that the regions that are disordered in soluble protein form stable helices when the protein is concentrated in condensates. These short helices create transient binding pockets that can be targeted with inhibitors when the receptor is in condensates. The researchers, working with the labs of Dr. Antoni Riera and Dr. Marianne Sadar, improved an experimental small molecule inhibitor to fit into these transient binding pockets.
The modified inhibitor showed significantly increased efficacy in aggressive, late-stage prostate cancer models. The researchers modified the chemical structure of the inhibitor to match the features of androgen receptor condensation, resulting in a tenfold increase in potency. This is particularly significant because castration-resistant prostate cancer, which is highly aggressive and resistant to current treatments, can benefit from more effective therapeutic options.
While these findings hold promise, further research is necessary before they can be translated into safe and effective therapeutics. The researchers believe that the principles they have uncovered may be applicable to other transcription factors as well, providing potential targets for various diseases.
Dr. Hnisz concludes that the idea of certain sequences within intrinsically disordered protein domains adopting a transiently stable structure in condensates is likely universal and applicable to other transcription factors. This discovery opens up new possibilities for targeting these important molecules in the treatment of different diseases.
1. Source: Coherent Market Insights, Public sources, Desk research
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