Executive SummaryThe proteasome is the cellular complex responsible for disposing of proteins that are either abnormal or old. Proteins that are destined for destruction by the proteasome are tagged with ubiquitin, a small polypeptide that enables proteins to enter the proteasome and be degraded. Because it helps regulate the level of proteins with important roles in cellular functions, the proteasome plays a key role in important processes such as DNA repair, cell cycle control, antigen processing and cellular differentiation.Academic researchers and the pharmaceutical industry have become increasingly interested in targeting the proteasome for therapeutic purposes. The rationale for this is that the proteasome helps regulate proteins that play important roles in pathogenesis of inflammatory diseases and cancer. One of the most important such proteins is nuclear factor-kappa B (NF-κB), a transcription factor that switches on genes for pro-inflammatory cytokines and also promotes cancer growth. The proteasome also regulates proteins that control the cell cycle, including cyclins, cell cycle inhibitors and p53. So, inhibiting the proteasome would be a way to inhibit NF-κB and cell cycle proteins as a strategy for therapy of inflammatory diseases – such as asthma, arthritis and psoriasis – and cancer. One further reason for targeting the proteasome for therapeutic purposes is that blocking proteasome activity causes an accumulation of ubiquitinylated misfolded proteins. This triggers the heat-shock response – a cellular defense mechanism that allows cells to withstand a volatile environment; this response could be useful in prevention of ischemic/reperfusion injury (tissue damage caused by sudden lack of blood flow).Boston-basedMillennium Pharmaceuticalsis leading the way in commercializing proteasome inhibitors for pharmaceutical use with two drugs in clinical trials – bortezomib and MLN-519. Bortezomib is a peptide boronate compound that is in phase III clinical trials for multiple myeloma and has received fast-track status from the US FDA. Millenium filed for US FDA approval of bortezomib in January 2003. MLN-519 is a lactacystin-type proteasome inhibitor that is in early clinical development for treatment of reperfusion injury, stroke and other neurological conditions. Millennium has out-licensed development of MLN-519 toPAION GmbH, a German biotech company, but retains an option to become reinvolved in development. Pennsylvania-basedCephalonand the Italian companyNovuspharmaare collaborating to discover and develop proteasome inhibitors for cancer therapy.