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

  • ACS Chem Neurosci. 2023 Jun 7;14(11):1963-1970. doi: 10.1021/acschemneuro.3c00096.
Melissa Guardigni  1 ,  Letizia Pruccoli  1 ,  Alan Santini  1 ,  Angela De Simone  2 ,  Matteo Bersani  2 ,  Francesca Spyrakis  2 ,  Flavia Frabetti  3 ,  Elisa Uliassi  4 ,  Vincenza Andrisano  1 ,  Barbara Pagliarani  1 ,  Paula Fernández-Gómez  5 ,  Valle Palomo  5  6 ,  Maria Laura Bolognesi  4 ,  Andrea Tarozzi  1 ,  Andrea Milelli  1
Affiliations
  • 1. Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • 2. Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Torino, Italy.
  • 3. Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Belmeloro 8, 40126 Bologna, Italy.
  • 4. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • 5. Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), C/Faraday 9, 28049 Madrid, Spain.
  • 6. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain.
PMID: 37218653 DOI: 10.1021/acschemneuro.3c00096
Abstract

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. Compound 1 emerged 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. PROTAC 1 significantly reduced the neurotoxicity induced by Aβ25-35 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-3β degraders as potential therapeutic agents.

Keywords
Alzheimer’s disease; chemical knockdown; glycogen synthase kinase 3β; protein degradation; proteolysis targeting chimeras.
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