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dc.contributor.authorPettinger, Jen_US
dc.contributor.authorCarter, Men_US
dc.contributor.authorJones, Ken_US
dc.contributor.authorCheeseman, MDen_US
dc.date.accessioned2019-11-15T14:28:32Z
dc.date.issued2019-12-06en_US
dc.identifier.citationJournal of medicinal chemistry, 2019, 62 (24), pp. 11383 - 11398en_US
dc.identifier.issn0022-2623en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3417
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/acs.jmedchem.9b01709en_US
dc.description.abstractThe covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. The success of this strategy has centered on exposed cysteine residues as nucleophiles but the low abundance of cysteine in the proteome has limited its application. We have recently reported our discovery that lysine-56 in the difficult-to-drug target HSP72 could form a covalent bond with a small-molecule inhibitor. We now disclose the optimization of these targeted covalent inhibitors using rational design. Essential to our optimization was the development of a new covalent fluorescence polarization assay, which allows for the direct measurement of the key kinetic parameter in covalent inhibitor design, kinact/KI, extrapolation of the underlying parameters, kinact and Ki, and direct comparison to reversible analogues. Using our approach, we demonstrate a >100-fold enhancement in covalent efficiency and key learnings in lysine-selective electrophile optimization.en_US
dc.formatPrint-Electronicen_US
dc.format.extent11383 - 11398en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.subjectHumansen_US
dc.subjectLysineen_US
dc.subjectMolecular Structureen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectKineticsen_US
dc.subjectHSP72 Heat-Shock Proteinsen_US
dc.subjectSmall Molecule Librariesen_US
dc.subjectDrug Discoveryen_US
dc.titleKinetic Optimization of Lysine-Targeting Covalent Inhibitors of HSP72.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jmedchem.9b01709en_US
rioxxterms.licenseref.startdate2019-12-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal of medicinal chemistryen_US
pubs.issue24en_US
pubs.notesNo embargoen_US
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 3
pubs.publication-statusPublisheden_US
pubs.volume62en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMedicinal Chemistry 3en_US
dc.contributor.icrauthorCheeseman, Matthewen_US


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