Qu Lailiang, Li Shang, Ji Limei, Luo Si, Ding Ming, Yin Fucheng, Wang Cheng, Luo Heng, Lu Dehua, Liu Xingchen, Peng Wan, Kong Lingyi, Wang Xiaobing
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2021 Dec 15;226:113889. doi: 10.1016/j.ejmech.2021.113889. Epub 2021 Oct 2.
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 (DC = 28.3 nM) and GSK3β (DC = 34.2 nM) in SH-SY5Y cells. SPR assay confirmed that PT-65 binds to GSK3β with high affinity (K = 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.
糖原合酶激酶3（GSK3）是治疗阿尔茨海默病的一个有前景的靶点。在此，我们描述了基于点击化学平台的一系列GSK3降解剂的设计与合成。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 = 28.3 nM）和GSK3β（DC = 34.2 nM）表现出最强的降解效力。表面等离子体共振（SPR）分析证实PT - 65与GSK3β具有高亲和力结合（K = 12.41 nM）。蛋白质组学研究表明PT - 65可选择性诱导GSK3降解。此外，PT - 65能以剂量依赖方式有效抑制GSK3β和Aβ介导的tau过度磷酸化，并保护SH - SY5Y细胞免受Aβ引起的细胞损伤。我们还证实PT - 65可抑制骨关节炎（OA）诱导的tau过度磷酸化，并改善阿尔茨海默病体内模型中的学习和记忆障碍。总之，PT - 65可能是治疗阿尔茨海默病的一个有前景的候选药物。
