Farrukh Vohidov,a Sarah E. Knudsen,a Paul G. Leonard,b Jun Ohata,a
Michael J. Wheadon,a Brian V. Popp,c John E. Ladburyd and Zachary T. Ball*a
Abstract
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).
Michael J. Wheadon,a Brian V. Popp,c John E. Ladburyd and Zachary T. Ball*a
aDepartment of Chemistry, Rice University, 6100 Main St., Houston, Texas, USA.
E-mail: zb1@rice.edu
bDepartment of Genomic Medicine, Core for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
cEugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, West Virginia, USA
dDepartment of Molecular and Cellular Biology, University of Leeds, LS2 9JT, UK
Chem. Sci., 2015, 6, 4778-4783
Received 2nd May 2015 Accepted 3rd June 2015
bDepartment of Genomic Medicine, Core for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
cEugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, West Virginia, USA
dDepartment of Molecular and Cellular Biology, University of Leeds, LS2 9JT, UK
Chem. Sci., 2015, 6, 4778-4783
Received 2nd May 2015 Accepted 3rd June 2015
DOI: 10.1039/c5sc01602a
http://pubs.rsc.org/en/content/articlelanding/2015/sc/c5sc01602a?iscitedby=True#!divAbstract
http://pubs.rsc.org/en/content/articlelanding/2015/sc/c5sc01602a?iscitedby=True#!divAbstract
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).
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