Natural Product and Synthetic Proteasome Inhibitors

Abstract

The ubiquitin—proteasome pathway has emerged as a major player in regulation several important signaling processes such as cell proliferation and inflammation. As a result, proteasome inhibitors are being intensely pursued as both molecular probes of proteasome biology and as therapeutic agents. Thus far, many proteasome inhibitors have been synthesized or isolated from natural sources, some of which are in clinical trial for cancer therapy. In this chapter, we discuss recent developments of both natural and synthetic proteasome inhibitors. Particular attention is focused on comparisons of the kinetic and/or biologic data for various proteasome inhibitors. Finally, we describe the design of novel proteasome inhibitors that target specific subunits of the proteasome.Key Wordsubiquitinproteasome inhibitorpeptide aldehydespeptide amidesvinyl sulfonesepoxy ketonesepoxomicinlactacystinboronic acidspolyphenolsmacrocyclic inhibitorsPGPH-specific inhibitorssubunit-specific inhibitors