Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

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dc.citation.journalTitleChemical Science
dc.contributor.authorVohidov, Farrukh
dc.contributor.authorKnudsen, Sarah E.
dc.contributor.authorLeonard, Paul G.
dc.contributor.authorOhata, Jun
dc.contributor.authorWheadon, Michael J.
dc.contributor.authorPopp, Brian V.
dc.contributor.authorLadbury, John E.
dc.contributor.authorBall, Zachary T.
dc.date.accessioned2015-06-15T18:57:49Z
dc.date.available2015-06-15T18:57:49Z
dc.date.issued2015
dc.description.abstractSrc-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(II) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(II) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 200 nM).
dc.identifier.citationVohidov, Farrukh, Knudsen, Sarah E., Leonard, Paul G., et al.. "Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors." <i>Chemical Science,</i> (2015) Royal Society of Chemistry: http://dx.doi.org/10.1039/C5SC01602A.
dc.identifier.doihttp://dx.doi.org/10.1039/C5SC01602A
dc.identifier.urihttps://hdl.handle.net/1911/80753
dc.language.isoeng
dc.publisherRoyal Society of Chemistry
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licence
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.titlePotent and selective inhibition of SH3 domains with dirhodium metalloinhibitors
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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