Browsing by Author "Wheadon, Michael J."
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Item Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors(Royal Society of Chemistry, 2015) Vohidov, Farrukh; Knudsen, Sarah E.; Leonard, Paul G.; Ohata, Jun; Wheadon, Michael J.; Popp, Brian V.; Ladbury, John E.; Ball, Zachary T.Src-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).