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 (K_D = 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.

GSK3是治疗阿尔茨海默病的有希望的靶点。在这里，我们描述了基于点击化学平台的一系列 GSK3 降解剂的设计和合成。获得了一系列高效的 GSK3 降解剂。其中，PT-65 在 SH-SY5Y 细胞中对 GSK3α (DC ₅₀  = 28.3 nM) 和 GSK3β (DC _{50 = 34.2 nM) 表现出最强的降解效力。}SPR 测定证实 PT-65 以高亲和力与 GSK3β 结合 (K _D = 12.41 纳米）。蛋白质组学研究表明，PT-65 可以选择性地诱导 GSK3 降解。此外，PT-65 可有效抑制 GSK3β 和 Aβ 介导的 tau 过度磷酸化，并以剂量​​依赖性方式保护 SH-SY5Y 细胞免受 Aβ 引起的细胞损伤。我们还证实，PT-65 可以抑制 OA 诱导的 tau 过度磷酸化并改善 AD 体内模型中的学习和记忆障碍。总之，PT-65 可能是治疗 AD 的有希望的候选药物。