Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease.

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 3β (GSK-3β), 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 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against HO and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound shows no lethality in a wt-zebrafish model (<100 μM) and high water solubility.