Brief Communication | Published:

Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor

Nature Chemical Biology volume 8, pages 141143 (2012) | Download Citation

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.

  • Compound C21H16FN3OS

    4-(4-(4-Fluorophenyl)-2-(4-(methylsulfinyl)phenyl)-1H-imidazol-5-yl)pyridine

  • Compound C31H37N5O3

    1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea

  • Compound C21H18N2O

    2-(2-Aminophenyl-amino)-10,11-dihydro-dibenzo[a,d]-cyclohepten-5-one

  • Compound C21H15F2NO

    2-(2,4-Difluorophenyl-amino)-10,11-dihydro-dibenzo[a,d]-cyclohepten-5-one

  • Compound C24H21F2NO4

    (R)-2-(2,4-Difluorophenylamino)-7-[2,3-dihydroxypropoxy]-10,11-dihydro-dibenzo[a,d]-cyclohepten-5-one

  • Compound C9H8O3

    6-Methoxyphtalide

  • Compound C9H8O4

    2-Formyl-5-methoxybenzoic acid

  • Compound C16H13ClO3

    2-(3-Chlorophenethenyl)-5-methoxy-benzoic acid

  • Compound C16H15ClO3

    2-(3-Chlorophenethyl)-5-methoxy-benzoic acid

  • Compound C16H13ClO2

    2-Chloro-7-methoxy-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one

  • Compound C15H11ClO2

    2-Chloro-7-hydroxy-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one

  • Compound C21H21ClO4

    (S)-2-Chloro-7-(1,2-isopropylidenglycer-3-yl)-10,11-dihydro-dibenzo[a,d]cyclohepten-5-one

  • Compound C27H25F2NO4

    (S)-2-(2,4-Difluorophenylamino)-7-(1,2-isopropylidenglycer-3-yl)-10,11-dihydro-dibenzo-[a,d]-cyclohepten-5-one

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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.

Author information

Affiliations

  1. Institute of Pharmacy, University of Tübingen, Tübingen, Germany.

    • Solveigh C Koeberle
    • , Stefan Fischer
    • , Verena Schattel
    •  & Stefan A Laufer
  2. Institute of Age Research, Fritz Lipmann Institute, Jena, Germany.

    • Solveigh C Koeberle
  3. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

    • Johannes Romir
    •  & Thilo Stehle
  4. Institute of Pharmacy, University of Jena, Jena, Germany.

    • Andreas Koeberle
    •  & Oliver Werz
  5. C-A-I-R Biosciences GmbH, Tübingen, Germany.

    • Wolfgang Albrecht
  6. Faculty of Chemistry – Chemical Biology, Technische Universität Dortmund, Dortmund, Germany.

    • Christian Grütter
    •  & Daniel Rauh
  7. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Thilo Stehle

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Thilo Stehle or Stefan A Laufer.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods and Supplementary Results

Excel files

  1. 1.

    Supplementary Table 2

    Selectivity Data of 3 (Kd = 7.6 nM for p38α) and Skepinone-L (5) (Kd = 1.5 nM for p38α)

  2. 2.

    Supplementary Table 3

    Inhibitory activity data of Skepinone-L (IC50 = 2.8 nM)

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DOI

https://doi.org/10.1038/nchembio.761

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