2. Academic Validation
  3. Discovery of novel harmine derivatives as potent, selective, and brain permeable GSK3β inhibitors with effective In vivo anti-AD activity

Discovery of novel harmine derivatives as potent, selective, and brain permeable GSK3β inhibitors with effective In vivo anti-AD activity

  • Eur J Med Chem. 2026 Feb 5:303:118389. doi: 10.1016/j.ejmech.2025.118389.
Wenjie Liu 1,  Limeng Wu 2,  Xi Zeng 3,  Huanhua Chen 4,  Xinyue Ning 5,  Xiaoyu Sun 6,  Wenqiang Xuan 6,  Ying Hao 6,  Hongli Jia 7,  Zhenshu Li 4,  Zonghe Xu 4,  Xinyu Li 4,  Zihua Xu 8,  Wenwu Liu 9,  Qingchun Zhao 10,  Shuang Hao 11
Affiliations

Affiliations

  • 1 College of Life and Health Sciences, Northeastern University, Shenyang, 110819, PR China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China.
  • 2 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 3 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China; National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, 400038, PR China.
  • 4 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 5 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 6 College of Life and Health Sciences, Northeastern University, Shenyang, 110819, PR China.
  • 7 State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
  • 8 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China.
  • 9 Department of Pharmacy, Peking University First Hospital, Beijing, 100034, PR China. Electronic address: sunny961010@163.com.
  • 10 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110000, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: zhaoqingchun1967@163.com.
  • 11 College of Life and Health Sciences, Northeastern University, Shenyang, 110819, PR China. Electronic address: haoshuang@mail.neu.edu.cn.
PMID: 41313964 DOI: 10.1016/j.ejmech.2025.118389
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Glycogen synthase kinase 3β (GSK3β), a key enzyme in tau phosphorylation, is a promising therapeutic target for AD. Herein, we employed a structure-based drug design strategy to develop a novel series of harmine derivatives as potent GSK3β inhibitors. Among them, compound 39a bearing an intramolecular hydrogen bond scaffold, showed potent GSK3β inhibition (IC50 = 0.37 nM), meanwhile maintaining remarkable kinase selectivity, including >25000-fold selectivity over dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a well-known target of β-carboline derivative harmine. It suppressed tau phosphorylation in Tau (P301L) 293T cells (EC50 = 0.06 ± 0.01 μM) and exhibited favorable blood-brain barrier permeability. Notably, 39a significantly attenuated cognitive deficits and tau hyperphosphorylation pathology in OA-induced C57BL/6J mice and 3 × Tg-AD mouse models, without causing spontaneous locomotor defects at therapeutic doses. Collectively, 39a emerges as a promising GSK3β inhibitor for probing GSK3β's role in AD pathogenesis and guiding anti-AD drug discovery.

Keywords

Alzheimer's disease; Blood-brain barrier permeability; GSK3β; Harmine; Tau phosphorylation; β-Carboline.

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