Inhibitors of the immunoproteasome: current status and future directions

Zachary Miller, Lin Ao, Kyung B.o. Kim, Wooin Lee

Research output: Contribution to journalReview articlepeer-review

76 Scopus citations

Abstract

The ubiquitin-proteasome system (UPS) plays a vital role in maintaining protein homeostasis and regulating numerous cellular processes. The proteasome, a multi-protease complex, is the key component of the UPS and has been validated as a therapeutic target by the FDA's approval of bortezomib and carfilzomib. These proteasome inhibitor drugs have substantially improved outcomes in patients with hematological malignancies and are currently being investigated for other types of cancer as well as several other diseases. These approved proteasome inhibitors target the catalytic activity of both the constitutive proteasome and the immunoproteasome indiscriminately, and their inhibitory effects on the constitutive proteasome in normal cells are believed to contribute to unwanted side effects. In addition, selective immunoproteasome inhibition has been proposed to have unique effects on other diseases, including those involving aberrant immune function. Initially recognized for its role in the adaptive immune response, the immunoproteasome is often upregulated in disease states such as inflammatory diseases and cancer, suggesting functions beyond antigen presentation. In an effort to explore the immunoproteasome as a potential therapeutic target in these diseases, the development of immunoproteasome-specific inhibitors has become the focus of recent studies. Owing to considerable efforts by both academic and industry groups, immunoproteasome-selective inhibitors have now been identified and tested against several disease models. These inhibitors also provide a valuable set of chemical tools for investigating the biological function of the immunoproteasome. In this review, we will focus on the recent efforts towards the development of immunoproteasome-selective inhibitors.

Original languageEnglish
Pages (from-to)4140-4151
Number of pages12
JournalCurrent Pharmaceutical Design
Volume19
Issue number22
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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