%0 Journal Article
%T Discovery of the First-in-Class GSK-3¦Â/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer¡¯s Disease
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00507
%X Several evidence pointed out the role of epigenetics in Alzheimer¡¯s disease (AD) revealing strictly relationships between epigenetic and ¡°classical¡± AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3¦Â (GSK-3¦Â), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H2O2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (<100 ¦ÌM) and high water solubility
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00507