Discovery Leads to Novel Cancer Medication Approach

Functioning as the "recycling center" in the cell, the proteasome regulates vitally important functions. When inhibited, the cell is left to suffocate in its own waste. Cancer cells are especially sensitive because they require the proteasome for their uncontrolled growth.

Now biochemists at the Techniche Universitaet Muenchen (TUM) have identified the lead structure of a new class of drugs that can disrupt the proteasome in an unusual way. New medication could be created on the basis of this previously unknown binding mechanism. The scientists report their results in the scientific journal Angewandte Chemie.

Due to its critical role in the development of cancer cells, the proteasome has been a focal point of cancer medication research efforts. When the proteasome becomes blocked, the growth of cancer cells slows down. The first drug implement this strategy, Bortezomib, generates revenues of over one billion dollars per year. The drug is used against multiple myeloma, a cancer of the bone marrow.
 
However, despite all of the success, proteasome inhibitors currently in use have one severe setback. Due to their high reactivity, they also attack other protein which impacts healthy cells in addition to their target cancer cells.

Led by lead researcher, Michael Groll of TU Munchen, the search for alternatives has now produced important results. The researchers conducted a high throughput screening, a process that involved an examination of over 200,000 potential agents capable of possessing proteasome inhibitors.

 Their resulting finding revealed a new structure with the so-called “N-hydroxyurea motif”, which reacts specifically with the active nucleus of the proteasome. The structure blocks the function of certain subunits of the protein complexes, which are catalytically active, and thus incapacitates the enzyme. As a result, the hydroxyurea structures are expected to work more specifically than other proteasome inhibitors and will likely cause fewer severe negative side effects.

The scientists already had a working knowledge of the basic hydroxyurea structure, although in a completely different context. The substance they examined is a derivative of the agent zileuton, which is used to treat asthma. The initial structure inhibited the proteasome very specifically, but not very effectively.
 
To modify the substance to work in lower concentrations for the purpose of medication, the researchers needed to understand how the structure blocks the proteasome. Using a crystal structure analysis, the researchers discovered that the hydroxyurea motif attacked the proteasome in a previously unknown manner. The reaction occurs due to unknown binding pockets that may serve as a starting point for the development of new medication agents.

The research team plans to improve the effectiveness of this newly discovered structure by continuing experiments on cell cultures.


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