Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins

J Med Chem. 2009 Oct 8;52(19):6024-31. doi: 10.1021/jm900720m.


Molecular disruption of the lipid carrier AFABP/aP2 in mice results in improved insulin sensitivity and protection from atherosclerosis. Because small molecule inhibitors may be efficacious in defining the mechanism(s) of AFABP/aP2 action, a chemical library was screened and identified 1 (HTS01037) as a pharmacologic ligand capable of displacing the fluorophore 1-anilinonaphthalene 8-sulfonic acid from the lipid binding cavity. The X-ray crystal structure of 1 bound to AFABP/aP2 revealed that the ligand binds at a structurally similar position to a long-chain fatty acid. Similar to AFABP/aP2 knockout mice, 1 inhibits lipolysis in 3T3-L1 adipocytes and reduces LPS-stimulated inflammation in cultured macrophages. 1 acts as an antagonist of the protein-protein interaction between AFABP/aP2 and hormone sensitive lipase but does not activate PPARgamma in macrophage or CV-1 cells. These results identify 1 as an inhibitor of fatty acid binding and a competitive antagonist of protein-protein interactions mediated by AFABP/aP2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Butyric Acid
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Fatty Acid-Binding Proteins / antagonists & inhibitors*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Ligands
  • Macrophages
  • Mice
  • Molecular Structure
  • Protein Binding
  • Small Molecule Libraries


  • Fatty Acid-Binding Proteins
  • Heterocyclic Compounds, 2-Ring
  • Ligands
  • Small Molecule Libraries
  • Butyric Acid

Associated data

  • PDB/3HK1