Abstract
Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, skepinone-L is a valuable probe for chemical biology research, and it may foster the development of a unique class of kinase inhibitors.
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Acknowledgements
We thank S. Luik, M Goettert and K. Bauer for biological testing. We thank M. Fecker, J.R. Simard, S. Mayer-Wrangowski and A. Richters for expert assistance during protein production and crystallization. D.R. is grateful for funds from the German Federal Ministry for Education (grant no. BMBF 01GS08104). We thank T. Joos, N. Schneiderhan-Marra, K. Hefner, M. Schmohl and G.M. Stein (Naturwissenschaftliches und Medizinisches Institut and Experimentelle und Diagnostische Immunologie Reutlingen) for cytokine profiling of skepinone-L in hPMBCs.
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Contributions
S.A.L. and T.S. initiated and supervised this study, S.C.K. conceived the chemical experiments, and S.C.K. and S.F. carried them out, J.R. conceived the experiment for X-ray structure of 2-amino-phenylamino-dibenzosuberone and carried it out. V.S. performed Molecular Modeling. C.G. solved the complex crystal structure of skepinone-L and carried out HeLa cell experiments with skepinone-L. A.K. conceived the cellular selectivity experiments and A.K and S.C.K. carried them out; W.A. conceived and carried out the studies for in vivo experiments. S.C.K., A.K., J.R., C.G. and W.A. designed and carried out the data analysis. S.C.K., A.K., S.F., D.R., T.S., O.W. and S.A.L. cowrote the paper. S.C.K. and J.R. contributed equally to this paper.
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Supplementary information
Supplementary Text and Figures
Supplementary Methods and Supplementary Results (PDF 536 kb)
Supplementary Table 2
Selectivity Data of 3 (Kd = 7.6 nM for p38α) and Skepinone-L (5) (Kd = 1.5 nM for p38α) (XLS 83 kb)
Supplementary Table 3
Inhibitory activity data of Skepinone-L (IC50 = 2.8 nM) (XLS 46 kb)
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Koeberle, S., Romir, J., Fischer, S. et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol 8, 141–143 (2012). https://doi.org/10.1038/nchembio.761
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DOI: https://doi.org/10.1038/nchembio.761
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