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Issue 10, 2012
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Exploiting nature's rich source of proteasome inhibitors as starting points in drug development

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Abstract

Cancer is the No. 2 cause of death in the Western world and one of the most expensive diseases to treat. Thus, it is not surprising, that every major pharmaceutical and biotechnology company has a blockbuster oncology product. In 2003, Millennium Pharmaceuticals entered the race with Velcade®, a first-in-class proteasome inhibitor that has been approved by the FDA for treatment of multiple myeloma and its sales have passed the billion dollar mark. Velcade®'s extremely toxic boronic acid pharmacophore, however, contributes to a number of severe side effects. Nevertheless, the launching of this product has validated the proteasome as a target in fighting cancer and further proteasome inhibitors have entered the market as anti-cancer drugs. Additionally, proteasome inhibitors have found application as crop protection agents, anti-parasitics, immunosuppressives, as well as in new therapies for muscular dystrophies and inflammation. Many of these compounds are based on microbial metabolites. In this review, we emphasize the important role of the structural elucidation of the various unique binding mechanisms of these compounds that have been optimized throughout evolution to target the proteasome. Based on this knowledge, medicinal chemists have further optimized these natural products, resulting in potential drugs with reduced off-target activities.

Graphical abstract: Exploiting nature's rich source of proteasome inhibitors as starting points in drug development

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Publication details

The article was received on 24 Aug 2011, accepted on 07 Oct 2011 and first published on 31 Oct 2011


Article type: Feature Article
DOI: 10.1039/C1CC15273D
Citation: Chem. Commun., 2012,48, 1364-1378
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    Exploiting nature's rich source of proteasome inhibitors as starting points in drug development

    M. A. Gräwert and M. Groll, Chem. Commun., 2012, 48, 1364
    DOI: 10.1039/C1CC15273D

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