High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors

Chandrasekhar V. Miduturu; Xianming Deng; Nicholas Kwiatkowski; Wannian Yang; Laurent Brault; Panagis Filippakopoulos; Eunah Chung; Qingkai Yang; Juerg Schwaller; Stefan Knapp; Randall W. King; Jiing Dwan Lee; Sanna Herrgard; Patrick Zarrinkar; Nathanael S. Gray

doi:10.1016/j.chembiol.2011.05.010

High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors

Chandrasekhar V. Miduturu, Xianming Deng, Nicholas Kwiatkowski, Wannian Yang, Laurent Brault, Panagis Filippakopoulos, Eunah Chung, Qingkai Yang, Juerg Schwaller, Stefan Knapp, Randall W. King, Jiing Dwan Lee, Sanna Herrgard, Patrick Zarrinkar, Nathanael S. Gray^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.

Original language	English (US)
Pages (from-to)	868-879
Number of pages	12
Journal	Chemistry and Biology
Volume	18
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2011.05.010
State	Published - Jul 29 2011

Funding

We thank Ambit Biosciences KINOMEscan high-throughput kinase selectivity profiling services for screening all the compounds against members of the human kinase. We thank Life Technologies Corporation, SelectScreen Kinase Profiling Service for performing enzymatic biochemical kinase profiling. Funding was provided by NIH grants: CA130876-03, HG005693-02, U54 HG006097-01 (N.S.G.), HD 23696-21 (E.C.), and GM66492 (R.W.K.). The Structural Genomics Consortium is a registered charity (1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. P.Z. and S.H. are former and current employees, respectively, at Ambit Biosciences. The kinase inhibitor profiling service KINOMEscan previously owned by Ambit Biosicences is now part of DiscoveRx Corporation.

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

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Miduturu, C. V., Deng, X., Kwiatkowski, N., Yang, W., Brault, L., Filippakopoulos, P., Chung, E., Yang, Q., Schwaller, J., Knapp, S., King, R. W., Lee, J. D., Herrgard, S., Zarrinkar, P., & Gray, N. S. (2011). High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors. Chemistry and Biology, 18(7), 868-879. https://doi.org/10.1016/j.chembiol.2011.05.010

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abstract = "Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that {"}high-throughput kinase profiling{"} is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.",

author = "Miduturu, {Chandrasekhar V.} and Xianming Deng and Nicholas Kwiatkowski and Wannian Yang and Laurent Brault and Panagis Filippakopoulos and Eunah Chung and Qingkai Yang and Juerg Schwaller and Stefan Knapp and King, {Randall W.} and Lee, {Jiing Dwan} and Sanna Herrgard and Patrick Zarrinkar and Gray, {Nathanael S.}",

note = "Funding Information: We thank Ambit Biosciences KINOMEscan high-throughput kinase selectivity profiling services for screening all the compounds against members of the human kinase. We thank Life Technologies Corporation, SelectScreen Kinase Profiling Service for performing enzymatic biochemical kinase profiling. Funding was provided by NIH grants: CA130876-03, HG005693-02, U54 HG006097-01 (N.S.G.), HD 23696-21 (E.C.), and GM66492 (R.W.K.). The Structural Genomics Consortium is a registered charity (1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. P.Z. and S.H. are former and current employees, respectively, at Ambit Biosciences. The kinase inhibitor profiling service KINOMEscan previously owned by Ambit Biosicences is now part of DiscoveRx Corporation. ",

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Miduturu, CV, Deng, X, Kwiatkowski, N, Yang, W, Brault, L, Filippakopoulos, P, Chung, E, Yang, Q, Schwaller, J, Knapp, S, King, RW, Lee, JD, Herrgard, S, Zarrinkar, P & Gray, NS 2011, 'High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors', Chemistry and Biology, vol. 18, no. 7, pp. 868-879. https://doi.org/10.1016/j.chembiol.2011.05.010

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AU - Miduturu, Chandrasekhar V.

AU - Deng, Xianming

AU - Kwiatkowski, Nicholas

AU - Yang, Wannian

AU - Brault, Laurent

AU - Filippakopoulos, Panagis

AU - Chung, Eunah

AU - Yang, Qingkai

AU - Schwaller, Juerg

AU - Knapp, Stefan

AU - King, Randall W.

AU - Lee, Jiing Dwan

AU - Herrgard, Sanna

AU - Zarrinkar, Patrick

AU - Gray, Nathanael S.

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N2 - Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.

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High-throughput kinase profiling: A more efficient approach toward the discovery of new kinase inhibitors

Abstract

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