Cancer treatment often involves the use of potent drugs designed to inhibit the growth of malignant cells. However, these drugs can sometimes cause severe side effects, limiting their effectiveness and posing additional health risks to patients. Recent research led by biochemist Caroline Kisker at the University of Würzburg has shed light on the underlying reasons for these adverse effects.
The Role of Ubiquitin and USP28
Ubiquitin is a small protein that plays a critical role in various cellular processes, including the stability and function of most proteins in the body. It acts by binding to other proteins, marking them for degradation. However, this process can be reversed by specific enzymes. One such enzyme, USP28, is known to stabilize proteins crucial for cell growth and division, which can also contribute to cancer progression.
To combat cancer, inhibitors of USP28 have been developed. These inhibitors are designed to disrupt cell division by blocking the USP28 enzyme, thereby reducing the stability of proteins involved in cancer growth. However, these inhibitors often target not only USP28 but also USP25, a closely related enzyme that is vital for the immune system.
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The Problem with Non-Specific Inhibitors
The dual targeting of USP28 and USP25 by these inhibitors leads to a range of severe side effects. These can include gastrointestinal problems, nerve damage, and even autoimmune diseases. The research conducted by Kisker’s team at the University of Würzburg has revealed the reason behind this issue: the structural similarities between USP28 and USP25.
Using X-ray crystallography, the team analyzed the structure of USP28 in combination with three inhibitors—AZ1, Vismodegib, and FT206. They discovered that the binding sites on USP28 and USP25 for these inhibitors are identical, making it impossible for the inhibitors to distinguish between the two enzymes. This non-specific binding results in unintended inhibition of USP25, leading to the aforementioned side effects.
Implications for Future Drug Development
The findings from the University of Würzburg provide a crucial foundation for developing more specific cancer drugs with fewer side effects. The goal is to modify existing inhibitors so that they target only USP28 or USP25, thereby increasing their specificity and reducing unwanted effects. This could be achieved by designing inhibitors that bind to less similar enzyme sites, enhancing their precision.
Looking Ahead
The development of more targeted inhibitors represents a significant step forward in cancer treatment. By improving the specificity of these drugs, researchers hope to minimize side effects and improve the overall effectiveness of cancer therapies. The ongoing research at the University of Würzburg holds promise for creating safer and more efficient treatments for cancer patients.
Molecular mechanisms
The research led by Caroline Kisker and her team at the University of Würzburg highlights the importance of understanding the molecular mechanisms behind drug interactions. By addressing the root causes of severe side effects, they are paving the way for the development of more precise and safer cancer treatments. This advancement underscores the critical need for continued research and innovation in the fight against cancer.
