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PROTAC-Induced Glycogen Synthase Kinase 3ß Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease.
Guardigni, Melissa; Pruccoli, Letizia; Santini, Alan; Simone, Angela De; Bersani, Matteo; Spyrakis, Francesca; Frabetti, Flavia; Uliassi, Elisa; Andrisano, Vincenza; Pagliarani, Barbara; Fernández-Gómez, Paula; Palomo, Valle; Bolognesi, Maria Laura; Tarozzi, Andrea; Milelli, Andrea.
Afiliação
  • Guardigni M; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • Pruccoli L; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • Santini A; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • Simone A; Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Torino, Italy.
  • Bersani M; Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Torino, Italy.
  • Spyrakis F; Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, 10125 Torino, Italy.
  • Frabetti F; Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Belmeloro 8, 40126 Bologna, Italy.
  • Uliassi E; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • Andrisano V; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • Pagliarani B; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
  • Fernández-Gómez P; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), C/Faraday 9, 28049 Madrid, Spain.
  • Palomo V; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), C/Faraday 9, 28049 Madrid, Spain.
  • Bolognesi ML; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain.
  • Tarozzi A; Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • Milelli A; Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
ACS Chem Neurosci ; 14(11): 1963-1970, 2023 06 07.
Article em En | MEDLINE | ID: mdl-37218653
Glycogen synthase kinase 3ß (GSK-3ß) 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-3ß degraders was designed and synthesized by linking two different GSK-3ß 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-3ß starting from 0.5 µM in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by Aß25-35 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-3ß degraders as potential therapeutic agents.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer / Neuroblastoma Limite: Humans Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer / Neuroblastoma Limite: Humans Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2023 Tipo de documento: Article