PROTACs suppression of GSK-3ß, a crucial kinase in neurodegenerative diseases.
Eur J Med Chem
; 210: 112949, 2021 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-33097303
ABSTRACT
Glycogen synthase kinase 3ß (GSK-3ß) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC50 values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3ß. Western-blot data showed compound PG21 can effectively degrade GSK-3ß in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 µM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3ß is mediated by the ubiquitin-proteasome system (UPS). In addition, PG21 protects against glutamate-induced cell death in HT-22 cells. As the first PROTAC example to degrade GSK-3ß protein, the present study has provided potential candidates for further investigation in the biological function of GSK-3ß protein and its association with diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Inhibidores Enzimáticos
/
Proteolisis
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Glucógeno Sintasa Quinasa 3 beta
Límite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
China