Proteasome inhibitors as therapeutic agents

Highly regulated intracellular proteolysis is necessary for cell-cycle progression and cell division. The ubiquitin–proteasome pathway (UPP) plays a central role in the degradation of proteins and has therefore become an important, novel therapeutic target for diseases involving cell proliferation, most notably cancer. Proteasome inhibitors were initially used as research tools in cell biology to characterise the properties of the UPP. It was later determined that proteasome inhibition induced cell-cycle arrest and programmed cell death (apoptosis) in cancer cells in vitro and could inhibit tumour growth in animal xenograft models. Several classes of molecules that have proteasome-inhibiting characteristics have been studied. The dipeptidyl boronic acid bortezomib (Velcade™ Millennium Pharmaceuticals, Inc.), formerly known as PS-341, LDP-341 and MLN-341, is a potent and specific inhibitor of the proteasome that holds promise as a potential human therapeutic. It is the first proteasome inhibitor to be examined in human clinical trials and according to preliminary Phase I and II data, the drug has exhibited both manageable toxicities and biological activity.