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Issue 8, 2015
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Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

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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).

Graphical abstract: Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

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Publication details

The article was received on 02 May 2015, accepted on 03 Jun 2015 and first published on 03 Jun 2015


Article type: Edge Article
DOI: 10.1039/C5SC01602A
Citation: Chem. Sci., 2015,6, 4778-4783
  • Open access: Creative Commons BY license
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    Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

    F. Vohidov, S. E. Knudsen, P. G. Leonard, J. Ohata, M. J. Wheadon, B. V. Popp, J. E. Ladbury and Z. T. Ball, Chem. Sci., 2015, 6, 4778
    DOI: 10.1039/C5SC01602A

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