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Next-generation proteasome inhibitors for cancer therapy

  • Author Footnotes
    1 J.E.P. and Z.M. equally contributed to this work.
    Ji Eun Park
    Footnotes
    1 J.E.P. and Z.M. equally contributed to this work.
    Affiliations
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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  • Author Footnotes
    1 J.E.P. and Z.M. equally contributed to this work.
    Zachary Miller
    Footnotes
    1 J.E.P. and Z.M. equally contributed to this work.
    Affiliations
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky
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  • Yearin Jun
    Affiliations
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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  • Wooin Lee
    Correspondence
    Reprint requests: Wooin Lee, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea;
    Affiliations
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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  • Kyung Bo Kim
    Correspondence
    Reprint requests: Kyung Bo Kim, Pharmaceutical Sciences, University of Kentucky, 789 South Limestone, Lexington, KY 40536-0596;
    Affiliations
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky
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  • Author Footnotes
    1 J.E.P. and Z.M. equally contributed to this work.
Published:March 26, 2018DOI:https://doi.org/10.1016/j.trsl.2018.03.002
      Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.

      Abbreviations:

      BTZ (bortezomib), CFZ (carfilzomib), C-L (caspase-like), CNS (central nervous system), CT-L (chymotrypsin-like), CYPs (cytochrome P450 enzymes), iP (immunoproteasome), IXZ (ixazomib), MM (multiple myeloma), OPZ (oprozomib), PD (pharmacodynamic), PI (proteasome inhibitor), PK (pharmacokinetic), T-L (trypsin-like), UPS (ubiquitin proteasome system)
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