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  3. Exploring Novel GSK-3β Inhibitors for Anti-Neuroinflammatory and Neuroprotective Effects: Synthesis, Crystallography, Computational Analysis, and Biological Evaluation

Exploring Novel GSK-3β Inhibitors for Anti-Neuroinflammatory and Neuroprotective Effects: Synthesis, Crystallography, Computational Analysis, and Biological Evaluation

  • ACS Chem Neurosci. 2024 Sep 4;15(17):3181-3201. doi: 10.1021/acschemneuro.4c00365.
Izabella Góral 1 2,  Tomasz Wichur 1,  Emilia Sługocka 1 2 3,  Przemysław Grygier 3 4,  Monika Głuch-Lutwin 5,  Barbara Mordyl 5,  Ewelina Honkisz-Orzechowska 6,  Natalia Szałaj 1,  Justyna Godyń 1,  Dawid Panek 1,  Paula Zaręba 1,  Anna Sarka 6,  Paweł Żmudzki 7,  Gniewomir Latacz 6,  Katarzyna Pustelny 8,  Adam Bucki 7,  Anna Czarna 3,  Filipe Menezes 9,  Anna Więckowska 1
Affiliations

Affiliations

  • 1 Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., Krakow 30-688, Poland.
  • 2 Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 16 Lazarza St., Krakow 31-530, Poland.
  • 3 Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, Krakow 30-387, Poland.
  • 4 Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, Krakow 30-348, Poland.
  • 5 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., Krakow 30-688, Poland.
  • 6 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., Krakow 30-688, Poland.
  • 7 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., Krakow 30-688, Poland.
  • 8 Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7 St., Krakow 30-387, Poland.
  • 9 Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
PMID: 39158934 DOI: 10.1021/acschemneuro.4c00365
Abstract

In the pathogenesis of Alzheimer's disease, the overexpression of glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes to the promotion of amyloid β and Tau Protein accumulation, as well as neuroinflammatory processes. Therefore, in the present study, we have designed, synthesized, and evaluated a new series of GSK-3β inhibitors based on the N-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound 36, demonstrating an IC50 of 70 nM against GSK-3β. Subsequently, through crystallography studies and quantum mechanical analysis, we elucidated its binding mode and identified the structural features crucial for interactions with the active site of GSK-3β, thereby understanding its inhibitory potency. Compound 36 was effective in the cellular model of hyperphosphorylated tau-induced neurodegeneration, where it restored cell viability after okadaic acid treatment and showed anti-inflammatory activity in the LPS model, significantly reducing NO, IL-6, and TNF-α release. In ADME-tox in vitro studies, we confirmed the beneficial profile of 36, including high permeability in PAMPA (Pe equals 9.4) and high metabolic stability in HLMs as well as lack of significant interactions with isoforms of the CYP Enzymes and lack of considerable cytotoxicity on selected cell lines (IC50 > 100 μM on HT-22 cells and 89.3 μM on BV-2 cells). Based on promising pharmacological activities and favorable ADME-tox properties, compound 36 may be considered a promising candidate for in vivo research as well as constitute a reliable starting point for further studies.

Keywords

ADME; Alzheimer’s disease; EDDA; anti-inflammatory activity; crystallography; glycogen synthase kinase-3β; neurodegeneration.

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