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.


Multiple Myeloma Unfold Protein Response Proteasome Inhibitor Mantle Cell Lymphoma Boronic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Bcl-2-associated X protein


B cell CLL/lymphoma-2


Bcl-2 homology 3


BH3-interacting domain death agonist


Bcl-2-interacting mediator of cell death




Cyclin-dependent kinase






Complete remission


Dose-limiting toxicity


Duration of response


Inhibitor of nuclear factor kappa B


Immunoproteasome-specific inhibitor


International Staging System


c-Jun-N-terminal kinase




Low molecular mass polypeptide


Myeloid cell leukemia sequence 1


Multicatalytic endopeptidase complex-like


Minor response


Maximum tolerated dose


Nuclear factor kappa B


Overall response rate


Peripheral blood mononuclear cells


Post-glutamyl peptide hydrolyzing also referred to as the caspase-like (C-L) activity


Partial remission


Tumor necrosis factor-mediated receptor activator of NF-κB ligand


Stringent CR


Second mitochondria-derived activator of caspases






Time to progression


Unfolded protein response


Very good PR



The author would like to acknowledge research support from the National Cancer Institute (P50-CA-142509, P01-CA-124787, R01-CA-102278, R01-CA-134786), as well as the Multiple Myeloma Research Foundation and The Leukemia & Lymphoma Society.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.The Department of Lymphoma & MyelomaThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Experimental TherapeuticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

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