Targeting Protein Degradation in Cancer Treatment

: The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

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Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Cancers ◽

10.3390/cancers13123079 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3079

Author(s):

Gabriel LaPlante ◽

Wei Zhang

Keyword(s):

Protein Degradation ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Proteasome Inhibitors ◽

Cancer Therapeutics ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

E3 Ligases ◽

Protein Levels ◽

Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

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Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases

Life ◽

10.3390/life11070607 ◽

2021 ◽

Vol 11 (7) ◽

pp. 607

Author(s):

Soonsil Hyun ◽

Dongyun Shin

Keyword(s):

Neurodegenerative Diseases ◽

Protein Degradation ◽

Drug Targets ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Therapeutic Modality ◽

Target Proteins ◽

Bifunctional Molecules ◽

Ubiquitin Proteasome ◽

Related Proteins

Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases.

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The Ubiquitin-Proteasome System and Memory: Moving Beyond Protein Degradation

The Neuroscientist ◽

10.1177/1073858418762317 ◽

2018 ◽

Vol 24 (6) ◽

pp. 639-651 ◽

Cited By ~ 11

Author(s):

Timothy J. Jarome ◽

Rishi K. Devulapalli

Keyword(s):

Protein Degradation ◽

Chromatin Remodeling ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Memory Formation ◽

Consolidation Process ◽

Future Studies ◽

Cellular Models ◽

Ubiquitin Proteasome

Cellular models of memory formation have focused on the need for protein synthesis. Recently, evidence has emerged that protein degradation mediated by the ubiquitin-proteasome system (UPS) is also important for this process. This has led to revised cellular models of memory formation that focus on a balance between protein degradation and synthesis. However, protein degradation is only one function of the UPS. Studies using single-celled organisms have shown that non-proteolytic ubiquitin-proteasome signaling is involved in histone modifications and DNA methylation, suggesting that ubiquitin and the proteasome can regulate chromatin remodeling independent of protein degradation. Despite this evidence, the idea that the UPS is more than a protein degradation pathway has not been examined in the context of memory formation. In this article, we summarize recent findings implicating protein degradation in memory formation and discuss various ways in which both ubiquitin signaling and the proteasome could act independently to regulate epigenetic-mediated transcriptional processes necessary for learning-dependent synaptic plasticity. We conclude by proposing comprehensive models of how non-proteolytic functions of the UPS could work in concert to control epigenetic regulation of the cellular memory consolidation process, which will serve as a framework for future studies examining the role of the UPS in memory formation.

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Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.736008 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yu Yang ◽

Xuan Zhou ◽

Xinpeng Liu ◽

Ruying Song ◽

Yiming Gao ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Protein Homeostasis ◽

Potential Therapeutic Target ◽

Cellular Processes ◽

Wide Range ◽

Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Accumulated evidence shows that FBXW7 is fundamental to neurological functions and especially implicated in neurodevelopment and the nosogenesis of neurodegeneration. In this review, we describe general features of FBXW7 gene and proteins, and mainly present recent findings that highlight the vital roles and molecular mechanisms of FBXW7 in neurodevelopment such as neurogenesis, myelination and cerebral vasculogenesis and in the pathogenesis of some typical neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Additionally, we also provide a prospect on focusing FBXW7 as a potential therapeutic target to rescue neurodevelopmental and neurodegenerative impairment.

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Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

Biomolecules ◽

10.3390/biom10050796 ◽

2020 ◽

Vol 10 (5) ◽

pp. 796 ◽

Cited By ~ 2

Author(s):

Kundlik Gadhave ◽

Prateek Kumar ◽

Shivani Kapuganti ◽

Vladimir Uversky ◽

Rajanish Giri

Keyword(s):

Intrinsically Disordered Protein ◽

Intrinsic Disorder ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

26S Proteasome ◽

Deubiquitinating Enzymes ◽

Intrinsically Disordered ◽

Anti Cancer ◽

Ubiquitin Proteasome ◽

Dependent Protein

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

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The therapeutic potential of deubiquitinating enzyme inhibitors

Biochemical Society Transactions ◽

10.1042/bst0380137 ◽

2010 ◽

Vol 38 (1) ◽

pp. 137-143 ◽

Cited By ~ 85

Author(s):

Frédéric Colland

Keyword(s):

Anticancer Agents ◽

Enzyme Inhibitors ◽

Therapeutic Potential ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Deubiquitinating Enzymes ◽

Promising Alternative ◽

Mantle Cell ◽

Ubiquitin Proteasome ◽

Ubiquitin Conjugation

Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin–proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade® (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.

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Ubiquitin-Dependent Proteolysis in Neurons

Physiology ◽

10.1152/nips.01408.2002 ◽

2003 ◽

Vol 18 (1) ◽

pp. 29-33 ◽

Cited By ~ 4

Author(s):

Lars Klimaschewski

Keyword(s):

Neurodegenerative Diseases ◽

Protein Degradation ◽

Current Knowledge ◽

Neurological Diseases ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Present Review ◽

Major Protein ◽

Ubiquitin Proteasome ◽

The Brain

Various studies identified the ubiquitin-proteasome system as the prime suspect in causing neurodegenerative diseases. The present review summarizes our current knowledge about the expression, regulation, and functions of this major protein degradation pathway in the brain, with particular reference to the pathogenesis of associated neurological diseases.

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Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

Open Biology ◽

10.1098/rsob.170007 ◽

2017 ◽

Vol 7 (4) ◽

pp. 170007 ◽

Cited By ~ 75

Author(s):

Piotr Bragoszewski ◽

Michal Turek ◽

Agnieszka Chacinska

Keyword(s):

Mitochondrial Dysfunction ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Cellular Level ◽

Mitochondrial Proteins ◽

Mitochondrial Activity ◽

Mitochondrial Proteome ◽

Transport Chain ◽

Ubiquitin Proteasome ◽

And Function

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level.

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DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.254 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii63-ii63

Author(s):

Lakshmi Bollu ◽

Derek Wainwright ◽

Lijie Zhai ◽

Erik Ladomersky ◽

Kristen Lauing ◽

...

Keyword(s):

Protein Degradation ◽

Time Course ◽

Immune Cell ◽

Enzyme Inhibitors ◽

Tumor Development ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Specific Protein ◽

Cell Functions

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a specific protein and recruit an E3 ubiquitin ligase that enhance proteasome-mediated degradation of the target protein. METHODS A library of ≥100 IDO-PROTACs were developed by joining BMS986205 (IDO binder) with a linker group to various E3-ligase ligands. Western blot analysis of PROTAC-induced IDO degradation was tested in vitro among multiple human and mouse GBM cell lines including U87, GBM6, GBM43 and GL261 along a time course ranging between 1–96 hours of treatment and at varying concentrations. The mechanism of IDO protein degradation was investigated using pharmacologic ligands that inhibit or compete with the proteasome-mediated protein degradation pathway. RESULTS Primary screening identified several IDO-PROTACs with IDO protein degradation potential. Secondary screening showed that our lead compound has a DC50 value of ~0.5µM with an ability to degrade IDO in all GBM cells analyzed, and an initial activity within 12 hours of treatment that extended for up to 96 hours. Mutating the CRBN-binding ligand, pretreatment with the ubiquitin proteasome system inhibitors MG132 or MLN4924 or using unmodified parental compound all inhibited IDO protein degradation. CONCLUSIONS This study developed an initial IDO-PROTAC technology that upon further optimization, can neutralize both IDO enzyme and non-enzyme immunosuppressive effects. When combined with other forms of immunotherapy, IDO-PROTACs have the potential to substantially enhance immunotherapeutic efficacy in patients with GBM.

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A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽

10.3390/cells10081929 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1929

Author(s):

Eva M. Huber ◽

Michael Groll

Keyword(s):

Cell Cycle Progression ◽

Therapeutic Potential ◽

Cell Signalling ◽

Selective Inhibition ◽

Ubiquitin Proteasome System ◽

Cellular Processes ◽

Chemical Structures ◽

Phase Ii Clinical Trials ◽

Ubiquitin Proteasome ◽

Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

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