Eberly College of Arts and Sciences
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).
Digital Commons Citation
Vohidov, Farrukh; Knudsen, Sarah E.; Leonard, Paul G.; Ohata, Jun; Wheadon, Michael J.; Popp, Brian V.; Ladbury, John E.; and Ball, Zachary T., "Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors" (2015). Faculty & Staff Scholarship. 2338.
Vohidov, F., Knudsen, S. E., Leonard, P. G., Ohata, J., Wheadon, M. J., Popp, B. V., Ladbury, J. E., & Ball, Z. T. (2015). Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors. Chemical Science, 6(8), 4778–4783. https://doi.org/10.1039/c5sc01602a