Glycogen synthase kinase 3β (GSK-3β) is a
serine/threonine
kinase and an attractive therapeutic target for Alzheimer’s
disease. Based on proteolysis-targeting chimera (PROTAC) technology,
a small set of novel GSK-3β degraders was designed and synthesized
by linking two different GSK-3β inhibitors, SB-216763 and tideglusib,
to pomalidomide, as E3 recruiting element, through linkers of different
lengths. Compound1emerged as the most effective PROTAC
being nontoxic up to 20 μM to neuronal cells and already able
to degrade GSK-3β starting from 0.5 μM in a dose-dependent
manner. PROTAC1significantly reduced the neurotoxicity
induced by Aβ25–35peptide and CuSO4in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging
features, PROTAC1may serve as a starting point to develop
new GSK-3β degraders as potential therapeutic agents.