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

Carina Julia Doler, Anna Migglautsch, Nicole Mayer, Elisabeth Fuchs, Martina Schweiger, Matthias Romauch,, Gernot Grabner, Rudolf Zechner, Robert Zimmermann, Rolf Breinbauer

Research output: Contribution to conferencePosterResearch

Abstract

During the last decades it has been shown that a deregulated fatty acid (FA) metabolism is closely linked to the emergence of dyslipidemic and metabolic disorders.1 Adipose Triglyceride lipase (ATGL), is the rate limiting enzyme in triglyzeride metabolism in adipocytes strongly determining the concentration of circulating FAs.1,2 In absence of ATGL, increased insulin sensitivity combined with impaired glucose tolerance and resistance to cancer associated cachexia related to increased white adipose tissue (WAT) lipolysis and proteasomal muscle degradation is reported, which make ATGL a potentially interesting drug target. Recently we reported about the first potent inhibitor of murine ATGL (IC50 = 0.7 µM). Atglistatin reduces fatty acid mobilization in vitro and in vivo in mice, but surprisingly shows little activity against human ATGL despite high sequence similarity (>95%) in the active site.2,3 Based on structure-activity relationship (SAR) we have gained insight into the binding pocket of ATGL and used this knowledge for the synthesis of selective inhibitors of hATGL. [1] N. Mayer, M. Schweiger, M.C. Melcher, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Bioorg. Med. Chem. 2015, 23, 2904-1916. [2] A. Lass, R. Zimmermann, M. Oberer, R. Zechner, Prog. Lip. Res. 2011, 11, 14-27. [3] N. Mayer, M. Schweiger, M. Romauch, G. Grabner, T. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. Höfler, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Nat. Chem. Biol. 2013, 9, 785-787. [4] S. Eder, S. Schauer, C. Diwoky, H. Temmel, B. Guertl, G. Gorkiewicz, K. P. Tamilarasan, P. Kumari, M. Trauner, R. Zimmermann, P. Vesely, G. Haemmerle, R. Zechner, G. Hoefler, Science 2011, 333, 233-238.
Original languageEnglish
Pages1-1
Number of pages1
Publication statusPublished - 28 Jun 2016
EventTetrahedron Symposium - Barcelona, Barcelona, Spain
Duration: 28 Jun 20161 Jul 2016

Conference

ConferenceTetrahedron Symposium
CountrySpain
CityBarcelona
Period28/06/161/07/16

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Lipase
Fatty Acids
White Adipose Tissue
Cachexia
Glucose Intolerance
Lipolysis
Structure-Activity Relationship
Adipocytes
Inhibitory Concentration 50
Insulin Resistance
Muscles
Enzymes
Pharmaceutical Preparations
Neoplasms

Cite this

Doler, C. J., Migglautsch, A., Mayer, N., Fuchs, E., Schweiger, M., Romauch, M., ... Breinbauer, R. (2016). Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL). 1-1. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.

Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL). / Doler, Carina Julia; Migglautsch, Anna; Mayer, Nicole; Fuchs, Elisabeth; Schweiger, Martina; Romauch, Matthias; Grabner, Gernot; Zechner, Rudolf; Zimmermann, Robert; Breinbauer, Rolf.

2016. 1-1 Poster session presented at Tetrahedron Symposium, Barcelona, Spain.

Research output: Contribution to conferencePosterResearch

Doler, CJ, Migglautsch, A, Mayer, N, Fuchs, E, Schweiger, M, Romauch, M, Grabner, G, Zechner, R, Zimmermann, R & Breinbauer, R 2016, 'Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL)' Tetrahedron Symposium, Barcelona, Spain, 28/06/16 - 1/07/16, pp. 1-1.
Doler CJ, Migglautsch A, Mayer N, Fuchs E, Schweiger M, Romauch, M et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL). 2016. Poster session presented at Tetrahedron Symposium, Barcelona, Spain.
Doler, Carina Julia ; Migglautsch, Anna ; Mayer, Nicole ; Fuchs, Elisabeth ; Schweiger, Martina ; Romauch, Matthias ; Grabner, Gernot ; Zechner, Rudolf ; Zimmermann, Robert ; Breinbauer, Rolf. / Development of small-molecule inhibitors targeting adipose triglyceride lipase (ATGL). Poster session presented at Tetrahedron Symposium, Barcelona, Spain.1 p.
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abstract = "During the last decades it has been shown that a deregulated fatty acid (FA) metabolism is closely linked to the emergence of dyslipidemic and metabolic disorders.1 Adipose Triglyceride lipase (ATGL), is the rate limiting enzyme in triglyzeride metabolism in adipocytes strongly determining the concentration of circulating FAs.1,2 In absence of ATGL, increased insulin sensitivity combined with impaired glucose tolerance and resistance to cancer associated cachexia related to increased white adipose tissue (WAT) lipolysis and proteasomal muscle degradation is reported, which make ATGL a potentially interesting drug target. Recently we reported about the first potent inhibitor of murine ATGL (IC50 = 0.7 µM). Atglistatin reduces fatty acid mobilization in vitro and in vivo in mice, but surprisingly shows little activity against human ATGL despite high sequence similarity (>95{\%}) in the active site.2,3 Based on structure-activity relationship (SAR) we have gained insight into the binding pocket of ATGL and used this knowledge for the synthesis of selective inhibitors of hATGL. [1] N. Mayer, M. Schweiger, M.C. Melcher, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Bioorg. Med. Chem. 2015, 23, 2904-1916. [2] A. Lass, R. Zimmermann, M. Oberer, R. Zechner, Prog. Lip. Res. 2011, 11, 14-27. [3] N. Mayer, M. Schweiger, M. Romauch, G. Grabner, T. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. H{\"o}fler, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Nat. Chem. Biol. 2013, 9, 785-787. [4] S. Eder, S. Schauer, C. Diwoky, H. Temmel, B. Guertl, G. Gorkiewicz, K. P. Tamilarasan, P. Kumari, M. Trauner, R. Zimmermann, P. Vesely, G. Haemmerle, R. Zechner, G. Hoefler, Science 2011, 333, 233-238.",
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AU - Doler, Carina Julia

AU - Migglautsch, Anna

AU - Mayer, Nicole

AU - Fuchs, Elisabeth

AU - Schweiger, Martina

AU - Romauch,, Matthias

AU - Grabner, Gernot

AU - Zechner, Rudolf

AU - Zimmermann, Robert

AU - Breinbauer, Rolf

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N2 - During the last decades it has been shown that a deregulated fatty acid (FA) metabolism is closely linked to the emergence of dyslipidemic and metabolic disorders.1 Adipose Triglyceride lipase (ATGL), is the rate limiting enzyme in triglyzeride metabolism in adipocytes strongly determining the concentration of circulating FAs.1,2 In absence of ATGL, increased insulin sensitivity combined with impaired glucose tolerance and resistance to cancer associated cachexia related to increased white adipose tissue (WAT) lipolysis and proteasomal muscle degradation is reported, which make ATGL a potentially interesting drug target. Recently we reported about the first potent inhibitor of murine ATGL (IC50 = 0.7 µM). Atglistatin reduces fatty acid mobilization in vitro and in vivo in mice, but surprisingly shows little activity against human ATGL despite high sequence similarity (>95%) in the active site.2,3 Based on structure-activity relationship (SAR) we have gained insight into the binding pocket of ATGL and used this knowledge for the synthesis of selective inhibitors of hATGL. [1] N. Mayer, M. Schweiger, M.C. Melcher, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Bioorg. Med. Chem. 2015, 23, 2904-1916. [2] A. Lass, R. Zimmermann, M. Oberer, R. Zechner, Prog. Lip. Res. 2011, 11, 14-27. [3] N. Mayer, M. Schweiger, M. Romauch, G. Grabner, T. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. Höfler, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Nat. Chem. Biol. 2013, 9, 785-787. [4] S. Eder, S. Schauer, C. Diwoky, H. Temmel, B. Guertl, G. Gorkiewicz, K. P. Tamilarasan, P. Kumari, M. Trauner, R. Zimmermann, P. Vesely, G. Haemmerle, R. Zechner, G. Hoefler, Science 2011, 333, 233-238.

AB - During the last decades it has been shown that a deregulated fatty acid (FA) metabolism is closely linked to the emergence of dyslipidemic and metabolic disorders.1 Adipose Triglyceride lipase (ATGL), is the rate limiting enzyme in triglyzeride metabolism in adipocytes strongly determining the concentration of circulating FAs.1,2 In absence of ATGL, increased insulin sensitivity combined with impaired glucose tolerance and resistance to cancer associated cachexia related to increased white adipose tissue (WAT) lipolysis and proteasomal muscle degradation is reported, which make ATGL a potentially interesting drug target. Recently we reported about the first potent inhibitor of murine ATGL (IC50 = 0.7 µM). Atglistatin reduces fatty acid mobilization in vitro and in vivo in mice, but surprisingly shows little activity against human ATGL despite high sequence similarity (>95%) in the active site.2,3 Based on structure-activity relationship (SAR) we have gained insight into the binding pocket of ATGL and used this knowledge for the synthesis of selective inhibitors of hATGL. [1] N. Mayer, M. Schweiger, M.C. Melcher, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Bioorg. Med. Chem. 2015, 23, 2904-1916. [2] A. Lass, R. Zimmermann, M. Oberer, R. Zechner, Prog. Lip. Res. 2011, 11, 14-27. [3] N. Mayer, M. Schweiger, M. Romauch, G. Grabner, T. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. Höfler, C. Fledelius, R. Zechner, R. Zimmermann, R. Breinbauer, Nat. Chem. Biol. 2013, 9, 785-787. [4] S. Eder, S. Schauer, C. Diwoky, H. Temmel, B. Guertl, G. Gorkiewicz, K. P. Tamilarasan, P. Kumari, M. Trauner, R. Zimmermann, P. Vesely, G. Haemmerle, R. Zechner, G. Hoefler, Science 2011, 333, 233-238.

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