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

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

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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