Development of small-molecule inhibitors targeting adipose triglyceride lipase (original) (raw)

• Brief Communication
• Published: 06 October 2013
• Martina Schweiger2 na1,
• Matthias Romauch2,
• Gernot F Grabner2,
• Thomas O Eichmann2,
• Elisabeth Fuchs1,
• Jakov Ivkovic1,
• Christoph Heier2,
• Irina Mrak2,
• Achim Lass2,
• Gerald Höfler3,
• Christian Fledelius4,
• Rudolf Zechner2,
• Robert Zimmermann2 &
• …
• Rolf Breinbauer1

Nature Chemical Biology volume 9, pages 785–787 (2013)Cite this article

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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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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 toRobert 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.

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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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• Received: 29 January 2013
• Accepted: 29 August 2013
• Published: 06 October 2013
• Issue Date: December 2013
• DOI: https://doi.org/10.1038/nchembio.1359

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