Title:Immunoproteasome-Selective Inhibitors: A Promising Strategy to Treat Hematologic Malignancies, Autoimmune and Inflammatory Diseases
Volume: 23
Issue: 12
Author(s): Roberta Ettari, Santo Previti, Alessandra Bitto, Silvana Grasso and Maria Zappalà
Affiliation:
Keywords:
immunoproteasome, core particles, immunoproteasome-selective inhibitors, hematologic malignancies,
autoimmune diseases, inflammatory disease
Abstract: The immunoproteasome is predominantly expressed in monocytes and lymphocytes
and is responsible for the generation of antigenic peptides for cell-mediated immunity.
Upon the exposure of inflammatory cytokines IFN-γ and TNF-α, constitutive subunits can
be replaced by the synthesis of the immuno-core particles β1i, β2i and β5i. Recent studies demonstrated that
the immunoproteasome function is not only limited to MHC class I presentation, but it is also implicated in a
number of pathological disorders including hematological malignancies, inflammatory and autoimmune diseases.
At present the commercially available proteasome inhibitors Bortezomib and Carfilzomib, which have
been validated in multiple myeloma and other diseases, appear to target both the constitutive and immunoproteasomes
indiscriminately. This lack of specificity may, in part, explain some of the side effects of these
agents. In contrast, by selectively targeting the immunoproteasome, it may be possible to keep the antimyeloma
and antilymphoma efficacy unchanged and, at the same time, to increase the therapeutic index. The aim
of this review article is to discuss the most promising immunoproteasome core particle-selective inhibitors
which have been developed in the recent years, with a particular attention to their structural features, mechanism
of action and therapeutic application.
