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- W3203780554 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 GSK3β (DC50 = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3β 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 GSK3β and Aβ mediated tau hyperphosphorylation in a dose-dependent manner and protect SH-SY5Y cells from Aβ 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." @default.
- W3203780554 created "2021-10-11" @default.
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- W3203780554 date "2021-12-01" @default.
- W3203780554 modified "2023-10-13" @default.
- W3203780554 title "Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease" @default.
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- W3203780554 doi "https://doi.org/10.1016/j.ejmech.2021.113889" @default.
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- W3203780554 hasPublicationYear "2021" @default.
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