Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 19, Pages 7021-7030Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.07.079
Keywords
Nuclear receptors; HNF4; Naphthofuran; Yeast one-hybrid system; Linoleic acid
Funding
- European Community [QLG1-CT-2001-01513, LSHM-CT-2006-037498]
- Region Bretagne [SIE 211-B3-11]
- Centre National pour la Recherche Scientifique
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Nuclear receptors are ligand-activated transcription factors involved in all major physiological functions of complex organisms. In this respect, they are often described as drugable targets for a number of pathological states including hypercholesterolemia and atherosclerosis. HNF4 alpha (NR2A1) is a recently 'deorphanized' nuclear receptor which is bound in vivo by linoleic acid, although this natural ligand does not seem to promote transcriptional activation. In mouse, HNF4 alpha is a major regulator of liver development and hepatic lipid metabolism and mutations in human have been linked to diabetes. Here, we have used a yeast one-hybrid system to identify small molecule activators of HNF4 alpha in a library of synthetic compounds and found one hit bearing a methoxy group branched on a nitronaphthofuran backbone. A collection of molecules deriving from the discovered hit was generated and tested for activity toward HNF4 alpha in yeast one-hybrid system. It was found that both the nitro group and a complete naphthofuran backbone were required for full activity of the compounds. Furthermore, adding a hydroxy group at position 7 of the minimal backbone led to the most active compound of the collection. Accordingly, a direct interaction of the hydroxylated compound with the ligand binding domain of HNF4 alpha was detected by NMR and thermal denaturation assays. When used in mammalian cell culture systems, these compounds proved to be highly toxic, except when methylated on the furan ring. One such compound was able to modulate HNF4 alpha-driven transcription in transfected HepG2C3A cells. These data indicate that HNF4 alpha activity can be modulated by small molecules and suggest new routes for targeting the receptor in humans. (C) 2009 Elsevier Ltd. All rights reserved.
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