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

Glycogen synthase kinase 3 ss (GSK-3 ss) 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 ss degraders was designed and synthesized by linking two different GSK-3 ss 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 ss starting from 0.5 mu M in a dose- dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by A ss 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 ss degraders as potential therapeutic agents. KEYWORDS: proteolysis targeting chimeras, glycogen synthase kinase 3 ss, Alzheimer's disease, chemical knockdown, protein degradation