Second-Generation Proteasome Inhibitors

The first-in-class proteasome inhibitor, bortezomib, has provided proof-of-concept for the therapeutic approach of proteasome inhibition in a number of malignancies. However, as we look to the future and to further improving upon the contributions of this class of drugs, we will need to consider optimizing activity in solid tumors, reducing peripheral neuropathy and utilizing more convenient routes of administration. A number of “second-generation” proteasome inhibitors have been identified and are now in preclinical and clinical development, including MLN9708, CEP-18770, carfilzomib, and salinosporamide A (NPI-0052). These agents differ from bortezomib in some of their key characteristics, and differences in their pharmacology may result in different activity and safety profiles. This chapter reviews the second-generation proteasome inhibitors, together with other potential therapeutic targets in the ubiquitin–proteasome system.