Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

Farrukh Vohidov; Sarah E. Knudsen; Paul G. Leonard; Jun Ohata; Michael J. Wheadon; Brian V. Popp; John E. Ladbury; Zachary T. Ball

doi:10.1039/C5SC01602A

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors†

Farrukh Vohidov,^a Sarah E. Knudsen,^a Paul G. Leonard,^b Jun Ohata,^a Michael J. Wheadon,^a Brian V. Popp,^c John E. Ladbury^d and Zachary T. Ball

*^a

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* Corresponding authors

^a Department of Chemistry, Rice University, 6100 Main St., Houston, Texas, USA
E-mail: zb1@rice.edu

^b Department of Genomic Medicine, Core for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

^c Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, West Virginia, USA

^d Department of Molecular and Cellular Biology, University of Leeds, UK

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).

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DOI: https://doi.org/10.1039/C5SC01602A
Article type: Edge Article
Submitted: 02 May 2015
Accepted: 03 Jun 2015
First published: 03 Jun 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry

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Chem. Sci., 2015,6, 4778-4783

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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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Chemical Science

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors†

Abstract

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Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

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