Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

Gernot F Grabner, Nikolaus Guttenberger, Nicole Mayer, Anna K Migglautsch-Sulzer, Christian Lembacher-Fadum, Nermeen Fawzy, Dominik Bulfon, Peter Hofer, Thomas Züllig, Lennart Hartig, Natalia Kulminskaya, Gabriel Chalhoub, Margarita Schratter, Franz P W Radner, Karina Preiss-Landl, Sarah Masser, Achim Lass, Rudolf Zechner, Karl Gruber, Monika ObererRolf Breinbauer*, Robert Zimmermann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)6237–6250
Number of pages14
JournalJournal of the American Chemical Society
Issue number14
Early online date1 Apr 2022
Publication statusPublished - 13 Apr 2022

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

Fields of Expertise

  • Human- & Biotechnology


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