Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.
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April 2013
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Research Article|
March 28 2013
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery
Yinghong Gao;
Yinghong Gao
*EMD Millipore Corporation, 10394 Pacific Center Ct., San Diego, CA 92121, U.S.A.
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Stephen P. Davies;
Stephen P. Davies
†Millipore (UK) Ltd., Dundee Technology Park, Dundee DD2 1SW, U.K.
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Martin Augustin;
Martin Augustin
†Millipore (UK) Ltd., Dundee Technology Park, Dundee DD2 1SW, U.K.
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Anna Woodward;
Anna Woodward
†Millipore (UK) Ltd., Dundee Technology Park, Dundee DD2 1SW, U.K.
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Umesh A. Patel;
Umesh A. Patel
1
‡EMD Millipore, 6 Research Park, St. Charles, MO 93304, U.S.A.
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Robert Kovelman;
Robert Kovelman
*EMD Millipore Corporation, 10394 Pacific Center Ct., San Diego, CA 92121, U.S.A.
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Kevin J. Harvey
Kevin J. Harvey
2
*EMD Millipore Corporation, 10394 Pacific Center Ct., San Diego, CA 92121, U.S.A.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
September 13 2012
Revision Received:
January 24 2013
Accepted:
February 12 2013
Accepted Manuscript online:
February 12 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 451 (2): 313–328.
Article history
Received:
September 13 2012
Revision Received:
January 24 2013
Accepted:
February 12 2013
Accepted Manuscript online:
February 12 2013
Citation
Yinghong Gao, Stephen P. Davies, Martin Augustin, Anna Woodward, Umesh A. Patel, Robert Kovelman, Kevin J. Harvey; A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J 15 April 2013; 451 (2): 313–328. doi: https://doi.org/10.1042/BJ20121418
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