PROTAC-Induced Glycogen Synthase Kinase 3ß Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease.
ACS Chem Neurosci
; 14(11): 1963-1970, 2023 06 07.
Article
em En
| MEDLINE
| ID: mdl-37218653
ABSTRACT
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.
Palavras-chave
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
País de afiliação:
Itália