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Proteasome inhibitors as experimental therapeutics of autoimmune diseases.

Verbrugge SE, Scheper RJ, Lems WF, de Gruijl TD, Jansen G - Arthritis Res. Ther. (2015)

Bottom Line: Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics.The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies.Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. c.s.e.verbrugge@umcutrecht.nl.

ABSTRACT
Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren's syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of proteasome inhibitors. Asterisks indicate that the compound has not been evaluated for potential anti-inflammatory properties.
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Fig3: Chemical structures of proteasome inhibitors. Asterisks indicate that the compound has not been evaluated for potential anti-inflammatory properties.

Mentions: The important role of the proteasome in the activation of NF-κB has initiated research to develop PIs for therapeutic interventions for chronic inflammatory diseases and cancer. In a recent historical overview, Goldberg [22] described the timeline of PI development starting more than 40 years ago. Original studies on biochemical mechanisms of protein degradation emerged with the development of MG-132, a peptide aldehyde that blocked proteasome function. About a decade ago, bortezomib (BTZ), a boronic acid peptide, was the first PI that was approved for treatment of therapy-refractory multiple myeloma [23]. Development of BTZ as an anti-inflammatory drug has taken a slower path, but preclinical evaluations are still ongoing [22]. Recent reviews by Huber and Groll [24], and Kisselev and colleagues [7] summarized chemical and crystallography data of BTZ and second-generation PIs designed to target and bind either reversibly or irreversibly to constitutive and/or immunoproteasomes. PIs can be grouped into seven classes: aldehydes, vinyl sulfones, vinylamides (syrbactins), boronates, α’,β’-epoxyketones, α-ketoaldehydes (glyoxals), and β-lactones [24]. Figure 3 and Table 1 provide an overview of the chemical structure and other features (class, target, route of administration) of PIs that are currently under clinical development. All of these PIs represent active site inhibitors, interacting with the amino-terminal Thr1 site of the proteasome catalytic subunits. Apart from these types of PIs, non-competitive PIs have also been developed, which bind to structural non-active subunits (for example, proteasome subunit alpha type, α-subunits) or to regulatory particles outside the proteasome catalytic core [25]. Hereafter, we further elaborate on active-site PIs under pre-clinical evaluation as anti-inflammatory agents.Figure 3


Proteasome inhibitors as experimental therapeutics of autoimmune diseases.

Verbrugge SE, Scheper RJ, Lems WF, de Gruijl TD, Jansen G - Arthritis Res. Ther. (2015)

Chemical structures of proteasome inhibitors. Asterisks indicate that the compound has not been evaluated for potential anti-inflammatory properties.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308859&req=5

Fig3: Chemical structures of proteasome inhibitors. Asterisks indicate that the compound has not been evaluated for potential anti-inflammatory properties.
Mentions: The important role of the proteasome in the activation of NF-κB has initiated research to develop PIs for therapeutic interventions for chronic inflammatory diseases and cancer. In a recent historical overview, Goldberg [22] described the timeline of PI development starting more than 40 years ago. Original studies on biochemical mechanisms of protein degradation emerged with the development of MG-132, a peptide aldehyde that blocked proteasome function. About a decade ago, bortezomib (BTZ), a boronic acid peptide, was the first PI that was approved for treatment of therapy-refractory multiple myeloma [23]. Development of BTZ as an anti-inflammatory drug has taken a slower path, but preclinical evaluations are still ongoing [22]. Recent reviews by Huber and Groll [24], and Kisselev and colleagues [7] summarized chemical and crystallography data of BTZ and second-generation PIs designed to target and bind either reversibly or irreversibly to constitutive and/or immunoproteasomes. PIs can be grouped into seven classes: aldehydes, vinyl sulfones, vinylamides (syrbactins), boronates, α’,β’-epoxyketones, α-ketoaldehydes (glyoxals), and β-lactones [24]. Figure 3 and Table 1 provide an overview of the chemical structure and other features (class, target, route of administration) of PIs that are currently under clinical development. All of these PIs represent active site inhibitors, interacting with the amino-terminal Thr1 site of the proteasome catalytic subunits. Apart from these types of PIs, non-competitive PIs have also been developed, which bind to structural non-active subunits (for example, proteasome subunit alpha type, α-subunits) or to regulatory particles outside the proteasome catalytic core [25]. Hereafter, we further elaborate on active-site PIs under pre-clinical evaluation as anti-inflammatory agents.Figure 3

Bottom Line: Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics.The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies.Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands. c.s.e.verbrugge@umcutrecht.nl.

ABSTRACT
Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren's syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.

No MeSH data available.


Related in: MedlinePlus