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dc.contributor.authorPettinger, J
dc.contributor.authorLe Bihan, Y-V
dc.contributor.authorWidya, M
dc.contributor.authorvan Montfort, RLM
dc.contributor.authorJones, K
dc.contributor.authorCheeseman, MD
dc.date.accessioned2017-04-05T10:00:33Z
dc.date.issued2017-03
dc.identifier.citationAngewandte Chemie (International ed. in English), 2017, 56 (13), pp. 3536 - 3540
dc.identifier.issn1433-7851
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/558
dc.identifier.eissn1521-3773
dc.identifier.doi10.1002/anie.201611907
dc.description.abstractThe stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.
dc.formatPrint-Electronic
dc.format.extent3536 - 3540
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleAn Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.
dc.typeJournal Article
dcterms.dateAccepted2017-02-03
rioxxterms.versionofrecord10.1002/anie.201611907
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAngewandte Chemie (International ed. in English)
pubs.issue13
pubs.notesNo embargo
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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublished
pubs.volume56en_US
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 3en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorCheeseman, Matthewen
dc.contributor.icrauthorLe Bihan, Yann-Vaien
dc.contributor.icrauthorPettinger, Jonathanen
dc.contributor.icrauthorVan Montfort, Roberten
dc.contributor.icrauthorJones, Keithen


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