Novel proteasome inhibitors

Proteasome inhibition is a rational approach to the therapy of multiple myeloma both alone and in combination with other agents, where proteasome inhibitors help induce chemosensitization and overcome drug resistance. These concepts were initially validated with laboratory-grade proteasome inhibitors and then with the clinically relevant peptide boronic acid bortezomib. A second generation of proteasome inhibitors is now being evaluated both preclinically and clinically, including carfilzomib, CEP-18770, marizomib, and MLN9708, among others. Though all of these agents target predominantly the chymotrypsin-like activity of the proteasome expressed by the β5 subunit, they also have novel and unique properties, including different chemistries, pharmacokinetics, proteasome binding characteristics, and other proteasome subunit specificities. Characterization of these agents has provided a strong rationale for their translation into the clinic, and initial studies suggest that at least several of them could become part of our future chemotherapeutic armamentarium against myeloma. In this chapter, these various properties of the so-called second-generation proteasome inhibitors will be examined, and the biological and clinical basis of their potential will be reviewed.