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PLoS Pathogens Dec 2021Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all... (Review)
Review
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Topics: Animals; Chagas Disease; Humans; Leishmaniasis; Mycobacterium tuberculosis; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34882737
DOI: 10.1371/journal.ppat.1010058 -
Nature Communications Nov 2022Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large...
Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Bortezomib; Proteomics; Apoptosis; Proteasome Endopeptidase Complex; Immunoglobulins; Deubiquitinating Enzymes; Ubiquitin-Specific Proteases
PubMed: 36357400
DOI: 10.1038/s41467-022-34654-2 -
Cell Chemical Biology Jun 2017While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical...
While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.
Topics: Enzyme Activation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; p38 Mitogen-Activated Protein Kinases
PubMed: 28644955
DOI: 10.1016/j.chembiol.2017.06.005 -
Seminars in Oncology Dec 2017Since 2003, the US Food and Drug Administration approval of bortezomib, a proteasome inhibitor, has changed the management of hematologic malignancies and dramatically... (Review)
Review
Since 2003, the US Food and Drug Administration approval of bortezomib, a proteasome inhibitor, has changed the management of hematologic malignancies and dramatically improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Since that time, two additional proteasome inhibitors (carfilzomib and ixazomib) have been approved, with other agents and combinations currently under investigation. Proteasomes degrade ubiquitinated proteins or substrates through the ubiquitin-proteasome pathway, a pathway that is utilized in multiple myeloma because of the high protein turnover with immunoglobulin production. Proteasome inhibitors exploit dependence on this pathway, halting protein degradation that ultimately results in apoptosis and cell death. Here we will discuss the structure of the proteasome and the mechanisms of action for proteasome inhibitors to further understand their role in hematologic malignancies.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Glycine; Hematologic Neoplasms; Humans; Lymphoma, Mantle-Cell; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Structure-Activity Relationship
PubMed: 29935898
DOI: 10.1053/j.seminoncol.2018.01.004 -
Blood Advances Feb 2023Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is...
Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is associated with a poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. We found that relapsed/refractory MM is characterized by a SUMO-high state, and high expression of the SUMO E1-activating enzyme (SAE1/UBA2) is associated with poor overall survival. Consistently, continuous treatment of MM cell lines with carfilzomib (CFZ) enhanced SUMO pathway activity. Treatment of MM cell lines with the SUMO E1-activating enzyme inhibitor subasumstat (TAK-981) showed synergy with CFZ in both CFZ-sensitive and CFZ-resistant MM cell lines, irrespective of the TP53 state. Combination therapy was effective in primary MM cells and in 2 murine MM xenograft models. Mechanistically, combination treatment with subasumstat and CFZ enhanced genotoxic and proteotoxic stress, and induced apoptosis was associated with activity of the prolyl isomerase PIN1. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel and potent strategy for the treatment of proteasome inhibitor-resistant MM.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Multiple Myeloma; Sumoylation; Proteasome Endopeptidase Complex; Apoptosis; Ubiquitin-Activating Enzymes; NIMA-Interacting Peptidylprolyl Isomerase
PubMed: 35917568
DOI: 10.1182/bloodadvances.2022007875 -
Translational Research : the Journal of... Aug 2018Over 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... (Review)
Review
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.
Topics: Antineoplastic Agents; Boron Compounds; Bortezomib; Drug Resistance, Neoplasm; Glycine; Humans; Neoplasms; Oligopeptides; Proteasome Inhibitors
PubMed: 29654740
DOI: 10.1016/j.trsl.2018.03.002 -
Bioscience Reports Feb 2022Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates....
Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.
Topics: Amides; Animals; Antineoplastic Agents; Azoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 35088066
DOI: 10.1042/BSR20212721 -
International Journal of Molecular... Dec 2017The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by... (Review)
Review
The treatment of organ failure on patients requires the transplantation of functional organs, from donors. Over time, the methodology of transplantation was improved by the development of organ preservation solutions. The storage of organs in preservation solutions is followed by the ischemia of the organ, resulting in a shortage of oxygen and nutrients, which damage the tissues. When the organ is ready for the transplantation, the reperfusion of the organ induces an increase of the oxidative stress, endoplasmic reticulum stress, and inflammation which causes tissue damage, resulting in a decrease of the transplantation success. However, the addition of proteasome inhibitor in the preservation solution alleviated the injuries due to the ischemia-reperfusion process. The proteasome is a protein structure involved in the regulation the inflammation and the clearance of damaged proteins. The goal of this review is to summarize the role of the proteasome and pharmacological compounds that regulate the proteasome in protecting the organs from the ischemia-reperfusion injury.
Topics: Endoplasmic Reticulum Stress; Food; Humans; Inflammation; Organ Preservation; Organ Transplantation; Oxidative Stress; Oxygen; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Reperfusion Injury
PubMed: 29301204
DOI: 10.3390/ijms19010106 -
Journal of Clinical Oncology : Official... Dec 2020Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation... (Randomized Controlled Trial)
Randomized Controlled Trial
Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial.
PURPOSE
Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.
PATIENTS AND METHODS
The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization.
RESULTS
Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4 9.4 months; hazard ratio [HR], 0.659; 95% CI, 0.542 to 0.801; < .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6 12.9 months; HR, 0.586; < .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8% 8.0%), vomiting (24.2% 4.3%), and diarrhea (23.2% 12.3%). There was no increase in new primary malignancies (5.2% 6.2%); rates of on-study deaths were 2.6% versus 2.2%.
CONCLUSION
Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
Topics: Aged; Antineoplastic Agents; Boron Compounds; Double-Blind Method; Female; Glycine; Humans; Maintenance Chemotherapy; Male; Middle Aged; Multiple Myeloma; Placebos; Progression-Free Survival; Proteasome Inhibitors; Stem Cell Transplantation; Treatment Outcome
PubMed: 33021870
DOI: 10.1200/JCO.20.02060 -
International Journal of Molecular... Oct 2021The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The... (Review)
Review
The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.
Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34769030
DOI: 10.3390/ijms222111595