Discovery and development of second-generation proteasome inhibitors

Proteasome inhibition is a validated therapeutic strategy for the treatment of B-cell neoplasms. The peptide boronate based inhibitor bortezomib has become an important tool in the armamentarium for the treatment of multiple myeloma (MM) and has spurred the development of new agents that target the catalytic activities of the proteasome. Five of these agents, representing three distinct chemical classes, have reached clinical testing. These compounds have properties similar to and distinct from bortezomib. Here, the preclinical activity and clinical development of these agents are reviewed with special attention given to comparisons with bortezomib.