PROTAC-Induced Glycogen Synthase Kinase 3 Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease

Glycogen synthase kinase 3 beta (GSK-3 beta) 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-3 beta degraders was designed and synthesized by linking two different GSK-3 beta inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound 1 emerged as the most effective PROTAC being nontoxic up to 20 mu M to neuronal cells and already able to degrade GSK-3 beta starting from 0.5 mu M in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by A beta 25-35 peptide and CuSO4 in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC 1 may serve as a starting point to develop new GSK-3 beta degraders as potential therapeutic agents.