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dc.contributor.authorCollins, I
dc.contributor.authorWang, H
dc.contributor.authorCaldwell, JJ
dc.contributor.authorChopra, R
dc.date.accessioned2017-02-01T12:32:45Z
dc.date.accessioned2017-03-24T15:04:25Z
dc.date.accessioned2018-07-04T12:52:21Z
dc.date.issued2017-03-15
dc.identifier.citationThe Biochemical journal, 2017, 474 (7), pp. 1127 - 1147
dc.identifier.issn0264-6021
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1971
dc.identifier.eissn1470-8728
dc.identifier.doi10.1042/bcj20160762
dc.description.abstractManipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel-Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology.
dc.formatElectronic
dc.format.extent1127 - 1147
dc.languageeng
dc.language.isoeng
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/404
dc.relation.replacesinternal/404
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/521
dc.relation.replacesinternal/521
dc.relation.replacesinternal/926
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/926
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectThalidomide
dc.subjectProteasome Endopeptidase Complex
dc.subjectPeptide Hydrolases
dc.subjectUbiquitin
dc.subjectImmunologic Factors
dc.subjectDrugs, Investigational
dc.subjectGene Expression
dc.subjectSubstrate Specificity
dc.subjectVon Hippel-Lindau Tumor Suppressor Protein
dc.subjectSmall Molecule Libraries
dc.subjectUbiquitination
dc.subjectDrug Discovery
dc.subjectMolecular Targeted Therapy
dc.subjectProteolysis
dc.subjectProteasome Inhibitors
dc.titleChemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
dc.typeJournal Article
dcterms.dateAccepted2017-01-16
rioxxterms.versionofrecord10.1042/bcj20160762
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-03-15
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Biochemical journal
pubs.issue7
pubs.notes12 months
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublished
pubs.volume474
pubs.embargo.terms12 months
pubs.oa-locationhttp://www.biochemj.org/content/474/7/1127.full-text.pdf
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
dc.contributor.icrauthorChopra, Rajeshen
dc.contributor.icrauthorWang, Hannahen
dc.contributor.icrauthorCollins, Ianen
dc.contributor.icrauthorCaldwell, Johnen


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