Other Proteasome Inhibitors

The involvement of the 20S proteasome in the degradation of critical intracellular regulatory proteins has suggested the potential use of proteasome inhibitors as novel therapeutic agents being applicable in many different disease indications. Early synthetic inhibitors of the 20S proeteasome were relatively nonspecific compounds but proved to be invaluable probes for improving our understanding of the ubiquitin/proteasomedependent degradation pathway in vitro. New classes of inhibitors that target this proteolytic enzyme have emerged in the last few years by combining traditional drug discovery approaches with new methods to find and optimize lead structures. This chapter reviews recent salient medicinal chemistry achievements in the design, synthesis, and biologic characterization of a variety of inhibitors of the 20S proteasome. These compounds are capable of modulating the subunit-specific proteolytic activities of the 20S proteosome in ways not previously possible. Examples have been selected to illustrate the impact of structural-based design and natural product screening in this area of research.