2. Academic Validation
  3. Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

  • J Am Chem Soc. 2022 Apr 13;144(14):6237-6250. doi: 10.1021/jacs.1c10836.
Gernot F Grabner 1,  Nikolaus Guttenberger 2,  Nicole Mayer 2,  Anna K Migglautsch-Sulzer 2,  Christian Lembacher-Fadum 2,  Nermeen Fawzy 1,  Dominik Bulfon 1,  Peter Hofer 1,  Thomas Züllig 1,  Lennart Hartig 1,  Natalia Kulminskaya 1,  Gabriel Chalhoub 1,  Margarita Schratter 1,  Franz P W Radner 1,  Karina Preiss-Landl 1,  Sarah Masser 1,  Achim Lass 1 3,  Rudolf Zechner 1 3 4,  Karl Gruber 1 3 4,  Monika Oberer 1 3 4,  Rolf Breinbauer 2 3,  Robert Zimmermann 1 3 4
Affiliations

Affiliations

  • 1 Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31/2, 8010 Graz, Austria.
  • 2 Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
  • 3 BioTechMed-Graz, Mozartgasse 12/2, 8010 Graz, Austria.
  • 4 BioHealth Field of Excellence, University of Graz, Universitätsplatz 3, 8010 Graz, Austria.
PMID: 35362954 DOI: 10.1021/jacs.1c10836
Abstract

Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride Lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including Insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148756
    98.67%, ATGL Inhibitor