Vohidov, FarrukhKnudsen, Sarah E.Leonard, Paul G.Ohata, JunWheadon, Michael J.Popp, Brian V.Ladbury, John E.Ball, Zachary T.2015-06-152015-06-152015Vohidov, 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.https://hdl.handle.net/1911/80753Src-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).engThis Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported LicenceJournal articlehttp://dx.doi.org/10.1039/C5SC01602A