Identification and characterization of a small molecule inhibitor of fatty acid binding proteins

Ann V. Hertzel, Kristina Hellberg, Joseph M. Reynolds, Andrew C. Kruse, Brittany E. Juhlmann, Anne J. Smith, Mark A. Sanders, Douglas H. Ohlendorf, Jill Suttles, David A. Bernlohr

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70 Scopus citations


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 PPARγ 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.

Original languageEnglish (US)
Pages (from-to)6024-6031
Number of pages8
JournalJournal of medicinal chemistry
Issue number19
StatePublished - Oct 8 2009


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