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dc.contributor.authorPettinger, J
dc.contributor.authorCarter, M
dc.contributor.authorJones, K
dc.contributor.authorCheeseman, MD
dc.date.accessioned2019-11-15T14:28:32Z
dc.date.issued2019-12-06
dc.identifier.citationJournal of medicinal chemistry, 2019, 62 (24), pp. 11383 - 11398
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3417
dc.identifier.eissn1520-4804
dc.identifier.doi10.1021/acs.jmedchem.9b01709
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.
dc.formatPrint-Electronic
dc.format.extent11383 - 11398
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectLysine
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectKinetics
dc.subjectHSP72 Heat-Shock Proteins
dc.subjectSmall Molecule Libraries
dc.subjectDrug Discovery
dc.titleKinetic Optimization of Lysine-Targeting Covalent Inhibitors of HSP72.
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acs.jmedchem.9b01709
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2019-12-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of medicinal chemistry
pubs.issue24
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/Medicinal Chemistry 3
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-statusPublished
pubs.volume62
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 3en_US
dc.contributor.icrauthorCheeseman, Matthewen


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