Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease.
Eur J Med Chem
; 226: 113889, 2021 Dec 15.
Article
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| MEDLINE
| ID: mdl-34649182
ABSTRACT
GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained. Among them, PT-65 exhibited most potent degradation potency against GSK3α (DC50 = 28.3 nM) and GSK3ß (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3ß with high affinity (KD = 12.41 nM). The proteomic study indicated that PT-65 could selectively induced GSK3 degradation. Moreover, PT-65 could effectively suppress GSK3ß and Aß mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aß caused cell damage. We also confirmed that PT-65 could suppress OA induced tau hyperphosphorylation and ameliorate learning and memory impairments in vivo model of AD. In summary, PT-65 might be a promising candidate for the treatment of AD.
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Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Fármacos Neuroprotectores
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Glucógeno Sintasa Quinasa 3
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Inhibidores Enzimáticos
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Descubrimiento de Drogas
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Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
China