MSK1 (mitogen- and stress-activated kinase 1) and MSK2 are nuclear protein kinases that regulate transcription downstream of the ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38α MAPKs (mitogen-activated protein kinases) via the phosphorylation of CREB (cAMP-response-element-binding protein) and histone H3. Previous studies on the function of MSKs have used two inhibitors, H89 and Ro 31-8220, both of which have multiple off-target effects. In the present study, we report the characterization of the in vitro and cellular properties of an improved MSK1 inhibitor, SB-747651A. In vitro, SB-747651A inhibits MSK1 with an IC50 value of 11 nM. Screening of an in vitro panel of 117 protein kinases revealed that, at 1 μM, SB-747651A inhibited four other kinases, PRK2 (double-stranded-RNA-dependent protein kinase 2), RSK1 (ribosomal S6 kinase 1), p70S6K (S6K is S6 kinase) (p70RSK) and ROCK-II (Rho-associated protein kinase 2), with a similar potency to MSK1. In cells, SB-747651A fully inhibited MSK activity at 5–10 μM. SB-747651A was found to inhibit the production of the anti-inflammatory cytokine IL-10 (interleukin-10) in wild-type, but not MSK1/2-knockout, macrophages following LPS (lipopolysaccharide) stimulation. Both SB-747651A and MSK1/2 knockout resulted in elevated pro-inflammatory cytokine production by macrophages in response to LPS. Comparison of the effects of SB-747651A, both in vitro and in cells, demonstrated that SB-747651A exhibited improved selectivity over H89 and Ro 31-8220 and therefore represents a useful tool to study MSK function in cells.
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Research Article|
December 14 2011
Characterization of the cellular action of the MSK inhibitor SB-747651A
Shaista Naqvi;
Shaista Naqvi
1
*MRC Protein Phosphorylation Unit, Sir James Black Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Andrew Macdonald;
*MRC Protein Phosphorylation Unit, Sir James Black Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Claire E. McCoy;
Claire E. McCoy
3
*MRC Protein Phosphorylation Unit, Sir James Black Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Joanne Darragh;
Joanne Darragh
*MRC Protein Phosphorylation Unit, Sir James Black Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Alastair D. Reith;
Alastair D. Reith
†External Alliances & Development, R&D China, GlaxoSmithKline Pharmaceuticals R&D, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
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J. Simon C. Arthur
J. Simon C. Arthur
4
*MRC Protein Phosphorylation Unit, Sir James Black Complex, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
4To whom correspondence should be addressed (email j.s.c.arthur@dundee.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 06 2011
Revision Received:
October 03 2011
Accepted:
October 05 2011
Accepted Manuscript online:
October 05 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 347–357.
Article history
Received:
June 06 2011
Revision Received:
October 03 2011
Accepted:
October 05 2011
Accepted Manuscript online:
October 05 2011
Citation
Shaista Naqvi, Andrew Macdonald, Claire E. McCoy, Joanne Darragh, Alastair D. Reith, J. Simon C. Arthur; Characterization of the cellular action of the MSK inhibitor SB-747651A. Biochem J 1 January 2012; 441 (1): 347–357. doi: https://doi.org/10.1042/BJ20110970
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