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Researchers at the University of Würzburg (JMU) have unveiled critical insights into the development of more precise anti-cancer drugs, potentially revolutionizing cancer treatment by reducing unwanted side effects. The small protein ubiquitin, integral to nearly all cellular processes, plays a crucial role in regulating protein stability and function. Enzymes such as USP28 and USP25, which interact with ubiquitin, are pivotal in this process.
USP28 is known to stabilize proteins essential for cell growth and division, including those involved in cancer proliferation. Consequently, inhibitors targeting USP28 have been created to disrupt this stability, aiming to hinder cancer cell division. These inhibitors are foundational to many anti-cancer drugs currently under development. However, a significant challenge has emerged: these inhibitors also target USP25, a closely related enzyme critical to the immune system. The non-specific action of these inhibitors poses severe side effects, ranging from gastrointestinal issues to nerve damage and autoimmune diseases, complicating their clinical application.
High Risk of Enzyme Confusion
Professor Caroline Kisker, Chair of Structural Biology at the Rudolf Virchow Centre and Vice President for Research and Young Scientists at JMU, explains the conundrum: “There is a high risk of confusion between USP28 and USP25. Our research shows that the two enzymes are very similar or even identical in many areas, including where the inhibitors act.”
Through X-ray crystallography, Kisker’s team analyzed USP28’s structure in combination with inhibitors “AZ1,” “Vismodegib,” and “FT206,” identifying the spatial binding sites. Further biochemical experiments revealed that USP25 shared identical inhibitor binding sites with USP28. “The inhibitors are therefore unable to distinguish where they bind,” Kisker notes. “This explains the non-specific effect.”
Towards More Precise Inhibitors
This discovery is pivotal for developing more specific drugs with fewer side effects. “Our structural biology data allows us to modify existing inhibitors so that they only work against either USP25 or USP28,” says Kisker. “We also aim to find inhibitors that bind to less similar enzyme sites, enhancing targeting precision.”
This breakthrough lays the groundwork for designing next-generation anti-cancer therapeutics with enhanced specificity and reduced adverse effects. The research was funded by the German Research Foundation (DFG) and conducted at the Rudolf Virchow Centre for Integrative and Translational Imaging, an interdisciplinary hub dedicated to understanding the molecular causes of health and disease.
The Rudolf Virchow Centre in Würzburg
The Rudolf Virchow Centre (RVZ) is a leading research institution at the University of Würzburg, focusing on visualizing elementary life processes across scales. Home to 13 translational research groups and approximately 100 researchers, the centre is at the forefront of investigating molecular health and disease mechanisms.
This research marks a significant step towards improving cancer treatments, emphasizing the importance of precise targeting in drug development to minimize side effects and enhance therapeutic efficacy.
