Identification of small molecule regulators of the nuclear receptor HNF4a based on naphthofuran scaffolds

publication · 10 years ago
by Le Remy Guevel, Frederik Oger, Aurelien Lecorgne, Zuzana Dudasova, Soizic Chevance, Arnaud Bondon, Peter Barath, Gerard Simonneaux, Gilles Salbert (Université de Rennes1)
Nuclear receptors are ligand-activated transcription factors involved in all major physiological funnctions of complex organisms. In this respect, they are often described as drugable targets for a number of pathological states including hypercholesterolemia and atherosclerosis. HNF4a (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, HNF4a 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 HNF4a 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 HNF4a 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 HNF4a 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 HNF4a-driven transcription in transfected HepG2C3A cells. These data indicate that HNF4a activity can be modulated by small molecules and suggest new routes for targeting the receptor in humans.
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