2. Academic Validation
  3. Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease

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. 2021 Dec 15:226:113889. doi: 10.1016/j.ejmech.2021.113889.
Lailiang Qu 1,  Shang Li 1,  Limei Ji 1,  Si Luo 1,  Ming Ding 1,  Fucheng Yin 1,  Cheng Wang 1,  Heng Luo 1,  Dehua Lu 1,  Xingchen Liu 1,  Wan Peng 1,  Lingyi Kong 2,  Xiaobing Wang 3
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: cpu_lykong@126.com.
  • 3 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. Electronic address: xbwang@cpu.edu.cn.
PMID: 34649182 DOI: 10.1016/j.ejmech.2021.113889
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.

Keywords

Alzheimer's disease; GSK3; PROTAC; Tau hyperphosphorylation.

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