Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

Marcus Bantscheff; Dirk Eberhard; Yann Abraham; Sonja Bastuck; Markus Boesche; Scott Hobson; Toby Mathieson; Jessica Perrin; Manfred Raida; Christina Rau; Valérie Reader; Gavain Sweetman; Andreas Bauer; Tewis Bouwmeester; Carsten Hopf; Ulrich Kruse; Gitte Neubauer; Nigel Ramsden; Jens Rick; Bernhard Kuster; Gerard Drewes

doi:10.1038/nbt1328

Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

Marcus Bantscheff, Dirk Eberhard, Yann Abraham, Sonja Bastuck, Markus Boesche, Scott Hobson, Toby Mathieson, Jessica Perrin, Manfred Raida, Christina Rau, Valérie Reader, Gavain Sweetman, Andreas Bauer, Tewis Bouwmeester, Carsten Hopf, Ulrich Kruse, Gitte Neubauer, Nigel Ramsden, Jens Rick, Bernhard KusterGerard Drewes

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

910 Scopus citations

Abstract

We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery.

Original language	English
Pages (from-to)	1035-1044
Number of pages	10
Journal	Nature Biotechnology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/nbt1328
State	Published - Sep 2007
Externally published	Yes

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Bantscheff, M., Eberhard, D., Abraham, Y., Bastuck, S., Boesche, M., Hobson, S., Mathieson, T., Perrin, J., Raida, M., Rau, C., Reader, V., Sweetman, G., Bauer, A., Bouwmeester, T., Hopf, C., Kruse, U., Neubauer, G., Ramsden, N., Rick, J., ... Drewes, G. (2007). Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotechnology, 25(9), 1035-1044. https://doi.org/10.1038/nbt1328

@article{d146f5ce326b4a0c93817fdbd2783437,

title = "Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors",

abstract = "We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery.",

author = "Marcus Bantscheff and Dirk Eberhard and Yann Abraham and Sonja Bastuck and Markus Boesche and Scott Hobson and Toby Mathieson and Jessica Perrin and Manfred Raida and Christina Rau and Val{\'e}rie Reader and Gavain Sweetman and Andreas Bauer and Tewis Bouwmeester and Carsten Hopf and Ulrich Kruse and Gitte Neubauer and Nigel Ramsden and Jens Rick and Bernhard Kuster and Gerard Drewes",

note = "Funding Information: This work was partially supported by a grant from the German Bundesministerium fuer Bildung und Forschung (BMBF BioChancePLUS grant 0313335A). We would like to thank Charles Cohen, Tim Edwards, David Middlemiss, Markus Schirle, David Simmons and Francis Wilson for helpful discussions and support. We are grateful to Birgit Duempelfeld, Eva-Maria Kashammer-Lorenz, Jana Krause, Anja Podszuweit, Tatjana Rudi and Thilo Werner for expert technical assistance, to Svenja Burckhardt and Cyrille Boussard for the synthesis of compounds, to Michael Rinner, Judith Schlegl and Marianna Stabilini for database and IT tool development, and to Frank Weisbrodt for help with the figures. We would also like to thank Oliver Hantschel and Giulio Superti-Furga for stimulating discussions and valuable comments on the manuscript.",

year = "2007",

month = sep,

doi = "10.1038/nbt1328",

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Bantscheff, M, Eberhard, D, Abraham, Y, Bastuck, S, Boesche, M, Hobson, S, Mathieson, T, Perrin, J, Raida, M, Rau, C, Reader, V, Sweetman, G, Bauer, A, Bouwmeester, T, Hopf, C, Kruse, U, Neubauer, G, Ramsden, N, Rick, J, Kuster, B & Drewes, G 2007, 'Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors', Nature Biotechnology, vol. 25, no. 9, pp. 1035-1044. https://doi.org/10.1038/nbt1328

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T1 - Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

AU - Bantscheff, Marcus

AU - Eberhard, Dirk

AU - Abraham, Yann

AU - Bastuck, Sonja

AU - Boesche, Markus

AU - Hobson, Scott

AU - Mathieson, Toby

AU - Perrin, Jessica

AU - Raida, Manfred

AU - Rau, Christina

AU - Reader, Valérie

AU - Sweetman, Gavain

AU - Bauer, Andreas

AU - Bouwmeester, Tewis

AU - Hopf, Carsten

AU - Kruse, Ulrich

AU - Neubauer, Gitte

AU - Ramsden, Nigel

AU - Rick, Jens

AU - Kuster, Bernhard

AU - Drewes, Gerard

N1 - Funding Information: This work was partially supported by a grant from the German Bundesministerium fuer Bildung und Forschung (BMBF BioChancePLUS grant 0313335A). We would like to thank Charles Cohen, Tim Edwards, David Middlemiss, Markus Schirle, David Simmons and Francis Wilson for helpful discussions and support. We are grateful to Birgit Duempelfeld, Eva-Maria Kashammer-Lorenz, Jana Krause, Anja Podszuweit, Tatjana Rudi and Thilo Werner for expert technical assistance, to Svenja Burckhardt and Cyrille Boussard for the synthesis of compounds, to Michael Rinner, Judith Schlegl and Marianna Stabilini for database and IT tool development, and to Frank Weisbrodt for help with the figures. We would also like to thank Oliver Hantschel and Giulio Superti-Furga for stimulating discussions and valuable comments on the manuscript.

PY - 2007/9

Y1 - 2007/9

N2 - We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery.

AB - We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery.

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U2 - 10.1038/nbt1328

DO - 10.1038/nbt1328

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AN - SCOPUS:34948875686

SN - 1087-0156

VL - 25

SP - 1035

EP - 1044

JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 9

ER -

Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

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