Bortezomib (Velcade) is the first drug in the proteasome inhibitor class of anti-cancer agents approved in the US in 2003 for the treatment of relapsed and refractory multiple myeloma. The proteasome is a multicatalytic threonine protease responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of several proteins involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the treatment with proteasome inhibitors results in decreased proliferation, induction of apoptosis, and sensitization of tumor cells against conventional chemotherapeutic agents and irradiation. The clinical and commercial (2006 US sales of US$ 220.5 mln) success of bortezomib has stimulated the search for next generation proteasome inhibitors with higher selectivity and oral availability. The first candidates are in clinical development followed by a number of projects in pre-IND stage and others in the preclinical R&D pipeline.

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