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

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 tur...

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Bibliographic Details
Published inCancers Vol. 13; no. 12; p. 3079
Main Authors LaPlante, Gabriel, Zhang, Wei
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 20.06.2021
MDPI
Subjects
Cancer
Cell cycle
Chimeras
Degradation
DNA damage
Enzymes
Genomes
Homeostasis
Metabolism
Multiple myeloma
Mutation
Polypeptides
Proteasome inhibitors
Proteasomes
Protein turnover
Proteins
Proteolysis
Regulation
Review
Signal transduction
Tumor necrosis factor-TNF
Tumorigenesis
Ubiquitin
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Abstract 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.
AbstractList Simple SummaryThe ubiquitin-proteasome system regulates multiple facets of protein homeostasis to modulate signal transduction in numerous biological processes. Not surprisingly, dysregulation of this delicately balanced system is frequently observed in cancer progression. In the past two decades, researchers in both academia and industry have made significant progress in developing small-molecule inhibitors targeting various components in the ubiquitin-proteasome system for cancer therapy. Here, we aim to provide a comprehensive summary of these efforts. Additionally, we overview the advancements of targeted protein degradation, a recently emerging drug discovery concept in cancer therapy.AbstractThe 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.
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.
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.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.
Author Zhang, Wei
LaPlante, Gabriel
AuthorAffiliation 2 CIFAR Azrieli Global Scholars Program, Canadian Institute for Advanced Research, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G1M1, Canada
1 Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, 50 Stone Rd E, Guelph, ON N1G2W1, Canada; glaplant@uoguelph.ca
AuthorAffiliation_xml – name: 1 Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, 50 Stone Rd E, Guelph, ON N1G2W1, Canada; glaplant@uoguelph.ca
– name: 2 CIFAR Azrieli Global Scholars Program, Canadian Institute for Advanced Research, MaRS Centre West Tower, 661 University Avenue, Toronto, ON M5G1M1, Canada
Author_xml – sequence: 1
  givenname: Gabriel
  surname: LaPlante
  fullname: LaPlante, Gabriel
– sequence: 2
  givenname: Wei
  orcidid: 0000-0001-5813-240X
  surname: Zhang
  fullname: Zhang, Wei
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Snippet The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation...
Simple SummaryThe ubiquitin-proteasome system regulates multiple facets of protein homeostasis to modulate signal transduction in numerous biological...
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crossref
SourceType Open Access Repository
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Enrichment Source
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StartPage 3079
SubjectTerms Cancer
Cell cycle
Chimeras
Degradation
DNA damage
Enzymes
Genomes
Homeostasis
Metabolism
Multiple myeloma
Mutation
Polypeptides
Proteasome inhibitors
Proteasomes
Protein turnover
Proteins
Proteolysis
Regulation
Review
Signal transduction
Tumor necrosis factor-TNF
Tumorigenesis
Ubiquitin
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Title Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
URI https://www.proquest.com/docview/2544958268
https://www.proquest.com/docview/2548413250
https://pubmed.ncbi.nlm.nih.gov/PMC8235664
Volume 13
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