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New class of drugs for the reversible inhibition of proteasomes
Date:11/22/2011

ave severe disadvantages. As a result of their high reactivity they attack other proteins, too, thereby damaging not only cancer cells but also other healthy cells.

The search for alternatives conducted by a group of scientists headed by Professor Michael Groll, who holds the Chair of Biochemistry in the Department of Chemistry at the TU Mnchen, in collaboration with Professor Robert Huber, Director Emeritus at the Max-Plank Institute of Biochemistry and Dr. Stefan Hillebrand from Bayer CropScience, has now borne fruit: In a high throughput screening, the scientists examined a substance library of 200,000 potential agents in their quest to identify proteasome inhibitors and they were successful. They identified a new structure with the so-called N-hydroxyurea motif, which reacts not only reversibly but above all specifically with the active nucleus of the proteasome. The structure inhibits the function of particular subunits of the protein complexes, which are catalytically active, and thus incapacitates the enzyme. Because of this property, the newly discovered hydroxyurea structures work more specifically than other proteasome inhibitors and are thus expected to lead to less severe adverse side effects.

The scientists were already familiar with the basic hydroxyurea structure, albeit in a completely different context. The substance in question is a derivative of the agent zileuton, which is used to treat asthma. Zileuton itself does not influence the proteasome, but its derivative, which had so far received little attention, does. "We have now found a completely new application for this previously known class of substances," explains Michael Groll. "This is of great advantage, because there are already clinical trials that give us first indications of how this class of substances behaves in the human body."

The initial structure originally discovered in the database inhibited the proteasome very specifically, but not terribly effectivel
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Contact: Dr. Andreas Battenberg
battenberg@zv.tum.de
49-892-891-0510
Technische Universitaet Muenchen
Source:Eurekalert  

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