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Abstract
The proteasome is a multisubunit enzyme complex that plays a central role in the regulation
of proteins that control cell-cycle progression and apoptosis, and has therefore become
an important target for anticancer therapy. Before a protein is degraded, it is first
flagged for destruction by the ubiquitin conjugation system, which ultimately results
in the attachment of a polyubiquitin chain on the target protein. The proteasome's
19S regulatory cap binds the polyubiquitin chain, denatures the protein, and feeds
the protein into the proteasome's proteolytic core. The proteolytic core is composed
of 2 inner beta rings and 2 outer alpha rings. The 2 beta rings each contain 3 proteolytic
sites named for their trypsin-like, post-glutamyl peptide hydrolase-like (PGPH) (i.e.,
caspase-like), or chymotrypsin-like activity. Inhibition of the proteasome results
in cell-cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition
of the proteasome via bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341)
had antitumor activity against numerous tumor types either alone or in combination
with conventional chemotherapeutic agents; these results provided the rationale for
a broad clinical trial program. Bortezomib is currently in phase III trials for myeloma
and is in early clinical development for numerous other tumor types.