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.
Keywords: Immunoproteasome, proteasome inhibitors, molecular probes, autoimmune disorders, cancer, drug development.
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