A DNA methyltransferase modulator inspired by peyssonenyne natural product structures.
Fiche publication
Date publication
décembre 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GRONEMEYER Hinrich
Tous les auteurs :
Garcia-Dominguez P, Weiss M, Lepore I, Alvarez R, Altucci L, Gronemeyer H, de Lera AR
Lien Pubmed
Résumé
A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5-azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8, but not by the DNMT inhibitor SGI-1027.
Référence
ChemMedChem. 2012 Dec;7(12):2101-12