scholarly journals Discovery of Therapeutic Deubiquitylase Effector Molecules

2014 ◽  
Vol 19 (7) ◽  
pp. 989-999 ◽  
Author(s):  
B. Nicholson ◽  
Suresh Kumar ◽  
S. Agarwal ◽  
M. J. Eddins ◽  
J. G. Marblestone ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Proteasome Inhibitors ◽  
Therapeutic Targets ◽  
Cysteine Proteases ◽  
Preclinical Development ◽  
E3 Ligases ◽  
The Past ◽  
Novel Drugs ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The approval of proteasome inhibitors bortezomib and carfilzomib and the E3 ligase antagonist thalidomide and its analogs, lenalidomide and pomalidomide, validates the ubiquitin–proteasome pathway as a source of novel drugs for treating cancer and, potentially, a variety of devastating illnesses, including inflammation, cardiovascular disease, and neurodegenerative disease. All elements of this critical regulatory pathway—the proteasome itself, E3 ligases (which conjugate ubiquitin to target proteins), and deubiquitylating enzymes (which deconjugate ubiquitin, reversing ligase action)—are potential therapeutic targets, and all have been worked on extensively during the past decade. No deubiquitylase inhibitors or activators have yet progressed to clinical trial, however, despite compelling target validation and several years of high-throughput screening and preclinical development of hits by numerous pharmaceutical companies, biotechnology organizations, and academic groups. The appropriateness of deubiquitylases as therapeutic targets in many disease areas is reviewed, followed by evidence that selective inhibitors of these cysteine proteases can be discovered. Because the lack of progress in drug-discovery efforts with deubiquitylases suggests a need for improved discovery methodologies, currently available platforms and strategies are analyzed, and improved or completely novel, unrelated approaches are considered in terms of their likelihood of producing clinically viable effectors of deubiquitylases.

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

Abstract 37: Centrosome Destabilization Through the Ubiquitin-Proteasome Pathway Regulates Proplatelet Production

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kellie R Machlus ◽  
Prakrith Vijey ◽  
Thomas Soussou ◽  
Joseph E Italiano
Keyword(s):  
Protein Degradation ◽  
Proteasome Inhibitors ◽  
Aurora Kinase ◽  
Proteasome Activity ◽  
Major Pathway ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Proplatelet Formation

Background: Proteasome inhibitors such as bortezomib, a chemotherapeutic used to treat multiple myeloma, induce thrombocytopenia within days of initiation. The mechanism for this thrombocytopenia has been tied to data revealing that proteasome activity is essential for platelet formation. The major pathway of selective protein degradation uses ubiquitin as a marker that targets proteins for proteolysis by the proteasome. This pathway is previously unexplored in megakaryocytes (MKs). Objectives: We aim to define the mechanism by which the ubiquitin-proteasome pathway affects MK maturation and platelet production. Results: Pharmacologic inhibition of proteasome activity blocks proplatelet formation in megakaryocytes. To further characterize how this degradation was occurring, we probed distinct ubiquitin pathways. Inhibition of the ubiquitin-activating enzyme E1 significantly inhibited proplatelet formation up to 73%. In addition, inhibition of the deubiquitinase proteins UCHL5 and USP14 significantly inhibited proplatelet formation up to 83%. These data suggest that an intact ubiquitin pathway is necessary for proplatelet formation. Proteomic and polysome analyses of MKs undergoing proplatelet formation revealed a subset of proteins decreased in proplatelet-producing megakaryocytes, consistent with data showing that protein degradation is necessary for proplatelet formation. Specifically, the centrosome stabilizing proteins Aurora kinase (Aurk) A/B, Tpx2, Cdk1, and Plk1 were decreased in proplatelet-producing MKs. Furthermore, inhibition of AurkA and Plk1, but not Cdk1, significantly inhibited proplatelet formation in vitro over 83%. Conclusions: We hypothesize that proplatelet formation is triggered by centrosome destabilization and disassembly, and that the ubiquitin-proteasome pathway plays a crucial role in this transformation. Specifically, regulation of the AurkA/Plk1/Tpx2 pathway may be key in centrosome integrity and initiation of proplatelet formation. Determination of the mechanism by which the ubiquitin-proteasome pathway regulates the centrosome and facilitates proplatelet formation will allow us to design better strategies to target and reverse thrombocytopenia.

The Ubiquitin Proteasome Pathway from Bench to Bedside

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 220-225 ◽  
Author(s):  
Robert Z. Orlowski
Keyword(s):  
Phase I ◽  
Hematological Malignancies ◽  
Expression Profiles ◽  
Proteasome Inhibitors ◽  
Rational Approach ◽  
Significant Activity ◽  
Ubiquitin Proteasome Pathway ◽  
Gene And Protein Expression ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.

scholarly journals An Ultra-High Throughput Cell-Based Screen for Wee1 Degradation Inhibitors

2010 ◽  
Vol 15 (8) ◽  
pp. 907-917 ◽  
Author(s):  
Franck Madoux ◽  
Scott Simanski ◽  
Peter Chase ◽  
Jitendra K. Mishra ◽  
William R. Roush ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Fusion Protein ◽  
Small Molecules ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cell Cycle Progression ◽  
Ubiquitin Proteasome Pathway ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The tyrosine kinase Wee1 is part of a key cellular sensing mechanism that signals completion of DNA replication, ensuring proper timing of entry into mitosis. Wee1 acts as an inhibitor of mitotic entry by phosphorylating cyclin-dependent kinase CDK1. Wee1 activity is mainly regulated at the protein level through its phosphorylation and subsequent degradation by the ubiquitin proteasome pathway. To facilitate identification of small molecules preventing Wee1 degradation, a homogeneous cell-based assay was developed using HeLa cells transiently transfected with a Wee1-luciferase fusion protein. To ensure ultra-high-throughput screening (uHTS) compatibility, the assay was scaled to a 1536-well plate format and cells were transfected in bulk and cryopreserved. This miniaturized homogeneous assay demonstrated robust performance, with a calculated Z′ factor of 0.65 ± 0.05. The assay was screened against a publicly available library of ~218,000 compounds to identify Wee1 stabilizers. Nonselective, cytotoxic, and promiscuous compounds were rapidly triaged through the use of a similarly formatted counterscreen that measured stabilization of an N-cyclin B-luciferase fusion protein, as well as execution of viability assessment in the parental HeLa cell line. This screening campaign led to the discovery of 4 unrelated cell-permeable small molecules that showed selective Wee1-luciferase stabilization with micromolar potency. One of these compounds, SID4243143 (ML 118), was shown to inhibit cell cycle progression, underscoring the importance of Wee1 degradation to the cell cycle. Results suggest that this uHTS approach is suitable for identifying selective chemical probes that prevent Wee1 degradation and generally applicable to discovering inhibitors of the ubiquitin proteasome pathway.

scholarly journals The importance of ubiquitin E3 ligases, SCF and APC/C, in human cancers

2015 ◽  
Vol 88 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Ovidiu Vasile Bochis ◽  
Bogdan Fetica ◽  
Catalin Vlad ◽  
Patriciu Achimas-Cadariu ◽  
Alexandru Irimie
Keyword(s):  
Cell Cycle ◽  
Anaphase Promoting Complex ◽  
E3 Ligases ◽  
Cyclin Dependent Kinases ◽  
Ubiquitin Proteasome Pathway ◽  
Complex Process ◽  
Target Therapies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

     A normal evolution of the cell-cycle phases consists of multiple consecutive events, which makes it a highly complex process. Its preservation is regulated by Cyclin-Cdks (cyclin-dependent kinases) interactions and protein degradation, which is often controlled by the ubiquitin-mediated proteolysis.The goal of this review is to emphasize the most important features of the regulation of the cell-cycle involved in cancerogenesis, by presenting the involvement of E3 ubiquitin ligases SCF (Skp1-Cul1-F-box protein) and APC/C (Anaphase-promoting complex/cyclosome) in human malignancies. Also, we discuss the importance of the ubiquitin proteasome pathway blockade in cancer treatment. We know that a better understanding of the regulatory biology of the cell cycle can lead to the development of new target therapies for cancer.

scholarly journals Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shansa Pranami E. Jayaweera ◽  
Sacheela Prasadi Wanigasinghe Kanakanamge ◽  
Dharshika Rajalingam ◽  
Gayathri N. Silva
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Biochemical Properties ◽  
Regulatory Proteins ◽  
Toxicity Profile ◽  
The Us ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication

2005 ◽  
Vol 45 (1) ◽  
pp. 465-476 ◽  
Author(s):  
Dharminder Chauhan ◽  
Teru Hideshima ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Protein Translation ◽  
26S Proteasome ◽  
Intracellular Protein ◽  
Cycle Growth ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade™), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.

Activity of Circulating Proteasomes Correlates with Clinical Behavior in Patients with Chronic Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4546-4546
Author(s):  
Wanlong Ma ◽  
Hagop Kantarjian ◽  
Amber Donahue ◽  
Xi Zhang ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Healthy Volunteers ◽  
Myeloid Leukemia ◽  
Proteasome Inhibitors ◽  
Continuous Variable ◽  
Peptidase Activity ◽  
Clinical Behavior ◽  
Ubiquitin Proteasome ◽  
Important Regulator ◽  
Proteasome Pathway

Abstract The ubiquitin-proteasome pathway is implicated in the pathogenesis of many malignancies and is an important regulator of cell proliferation, apoptosis, DNA repair, and the stress response. Free circulating proteasomes have been reported in the plasma and sera of cancer patients. We measured proteasome peptidase activity in the plasma of patients with chronic myeloid leukemia (CML) and correlated these findings with clinical behaviour. Plasma samples from apparently healthy volunteers (n = 92) and patients in the chronic (n = 104) or accelerated/blast phase (n = 56) of CML were analysed with fluorogenic kinetic assays. Using peptide-AMC (7-amino-4-methylcoumaran) substrates, we measured the three reported proteasome enzymatic activities: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L). All proteasome activities were significantly higher in CML patients than in healthy volunteers. Extensive characterization of proteasome activities revealed correlations between levels or ratios of specific peptidase activities and disease phase, progression, aggressiveness, and survival. High Ch-L activity correlated with shorter survival in both CP (P=0.037) and Acc/Bl phase (P=0.047). Patients in CP and a ratio of Cas-L: Tr-L activity >1.48 had significantly shorter survival (P=0.03). Cas-L: Tr-L activity ratio was predictor of survival in Acc/Bl patients as a continuous variable. These findings suggest that proteasome activity in the plasma of CML patients reflects disease activity and can be used as a biomarker for predicting clinical behavior. Studies exploring the role of proteasome inhibitors in CML are therefore warranted.

scholarly journals Clogging the Ubiquitin-Proteasome Machinery with Marine Natural Products: Last Decade Update

Marine Drugs ◽  
2018 ◽  
Vol 16 (12) ◽  
pp. 467 ◽  
Author(s):  
Gerardo Della Sala ◽  
Francesca Agriesti ◽  
Carmela Mazzoccoli ◽  
Tiziana Tataranni ◽  
Valeria Costantino ◽  
...  
Keyword(s):  
Cell Death ◽  
High Throughput Screening ◽  
Marine Invertebrates ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
Biological Properties ◽  
Marine Natural Product ◽  
Cell Death Pathways ◽  
Central Protein ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome pathway (UPP) is the central protein degradation system in eukaryotic cells, playing a key role in homeostasis maintenance, through proteolysis of regulatory and misfolded (potentially harmful) proteins. As cancer cells produce proteins inducing cell proliferation and inhibiting cell death pathways, UPP inhibition has been exploited as an anticancer strategy to shift the balance between protein synthesis and degradation towards cell death. Over the last few years, marine invertebrates and microorganisms have shown to be an unexhaustive factory of secondary metabolites targeting the UPP. These chemically intriguing compounds can inspire clinical development of novel antitumor drugs to cope with the incessant outbreak of side effects and resistance mechanisms induced by currently approved proteasome inhibitors (e.g., bortezomib). In this review, we report about (a) the role of the UPP in anticancer therapy, (b) chemical and biological properties of UPP inhibitors from marine sources discovered in the last decade, (c) high-throughput screening techniques for mining natural UPP inhibitors in organic extracts. Moreover, we will tell about the fascinating story of salinosporamide A, the first marine natural product to access clinical trials as a proteasome inhibitor for cancer treatment.

scholarly journals Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19

2020 ◽  
Vol 21 (10) ◽  
pp. 3492 ◽  
Author(s):  
Valentino Clemente ◽  
Padraig D’Arcy ◽  
Martina Bazzaro
Keyword(s):  
Immune Response ◽  
Cysteine Proteases ◽  
Cell Immune Response ◽  
Deubiquitinating Enzymes ◽  
Improve Patient Survival ◽  
Replicase Proteins ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Improve Patient

Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host’s immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.

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