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Development of small-molecule inhibitors targeting adipose triglyceride lipase

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Abstract

Adipose triglyceride lipase (ATGL) is rate limiting in the mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo.

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Figure 1: Development of ATGL inhibitors and inhibition of lipolysis in vitro.
Figure 2: Inhibition of lipolysis in vivo and tissue distribution of Atglistatin.

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Acknowledgements

This work was funded by the Austrian Science Fund (FWF) projects (W901-B05 DK Molecular Enzymology (R. Zimmermann, R.B.), Translational Program TRP4 (R. Zimmermann), Wittgenstein Award 2007 (grant no. Z136, R. Zechner)) and by the Forschungsförderungsgesellschaft und Bundesministerium für Wissenschaft und Forschung (Austrian Genome Project GEN-AU: Genomics of Lipid-Associated Disorders (GOLD, R. Zechner, R. Zimmermann) and Platform for Chemical Biology in Austria (PLACEBO, R.B.)). We are grateful to B. Grumm and B. Wölfl for skillful help in the synthesis of Atglistatin. Furthermore, we thank P. Jacobsen and H. Tornqvist from Novo Nordisk for helpful discussions and for the provision of lead compounds.

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Author notes

  1. Nicole Mayer and Martina Schweiger: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Organic Chemistry, Graz University of Technology, Graz, Austria

    Nicole Mayer, Elisabeth Fuchs, Jakov Ivkovic & Rolf Breinbauer

  2. Institute of Molecular Biosciences, University of Graz, Graz, Austria

    Martina Schweiger, Matthias Romauch, Gernot F Grabner, Thomas O Eichmann, Christoph Heier, Irina Mrak, Achim Lass, Rudolf Zechner & Robert Zimmermann

  3. Institute of Pathology, Medical University of Graz, Graz, Austria

    Gerald Höfler

  4. Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark

    Christian Fledelius

Authors
  1. Nicole Mayer
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  2. Martina Schweiger
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  3. Matthias Romauch
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  4. Gernot F Grabner
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  5. Thomas O Eichmann
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  6. Elisabeth Fuchs
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  7. Jakov Ivkovic
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  8. Christoph Heier
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  9. Irina Mrak
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  10. Achim Lass
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  11. Gerald Höfler
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  12. Christian Fledelius
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  13. Rudolf Zechner
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  14. Robert Zimmermann
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  15. Rolf Breinbauer
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Contributions

R. Zimmermann, R.B., R. Zechner, G.H. and C.F. conceived the study design. N.M., M.S., M.R., T.O.E., J.I., E.F., G.F.G., A.L., C.H. and I.M. performed the experiments. R. Zimmermann and R.B. analyzed the data and wrote the paper. All of the authors read, revised and approved the manuscript.

Corresponding authors

Correspondence to Robert Zimmermann or Rolf Breinbauer.

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Competing interests

N.M., M.S., M.R., R. Zimmermann and R.B. have filed for a patent on lipase inhibitors.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1, Supplementary Figures 1–9 and Supplementary Note. (PDF 3322 kb)

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Mayer, N., Schweiger, M., Romauch, M. et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nat Chem Biol 9, 785–787 (2013). https://doi.org/10.1038/nchembio.1359

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