Synthesis and pharmacology of proteasome inhibitors

Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges. The ubiquitin-proteasome system controls fundamental processes such as cell cycle regulation, DNA repair, apoptosis, and immune and inflammatory responses, as well as hereditary disorders such as cystic fibrosis. This Review covers the synthesis of the most important proteasome inhibitors as well as their mode of action and clinical development.