8QJI

Crystal structure of GSK3b in complex with N-(4-(5-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)pyridin-2-yl)cyclopropanecarboxamide inhibitor (TW362)

Summary for 8QJI

• Entry DOI: 10.2210/pdb8qji/pdb
• Descriptor: Glycogen synthase kinase-3 beta, N-[4-[5-(1,2,4-oxadiazol-3-yl)thiophen-2-yl]pyridin-2-yl]cyclopropanecarboxamide (3 entities in total)
• Functional Keywords: tau phosphorylation, kinase inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41896.99

Authors

Slugocka, E.A.,Grygier, P.,Wichur, T.,Czarna, A.,Wieckowska, A. (deposition date: 2023-09-13, release date: 2024-09-04, Last modification date: 2024-10-16)

Primary citation

Goral, I.,Wichur, T.,Slugocka, E.,Grygier, P.,Gluch-Lutwin, M.,Mordyl, B.,Honkisz-Orzechowska, E.,Szalaj, N.,Godyn, J.,Panek, D.,Zareba, P.,Sarka, A.,Zmudzki, P.,Latacz, G.,Pustelny, K.,Bucki, A.,Czarna, A.,Menezes, F.,Wieckowska, A.
Exploring Novel GSK-3 beta Inhibitors for Anti-Neuroinflammatory and Neuroprotective Effects: Synthesis, Crystallography, Computational Analysis, and Biological Evaluation.
Acs Chem Neurosci, 15:3181-3201, 2024

PubMed 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 -(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound , demonstrating an IC 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 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 including high permeability in PAMPA ( 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 (IC > 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 may be considered a promising candidate for in vivo research as well as constitute a reliable starting point for further studies.

PubMed: 39158934
DOI: 10.1021/acschemneuro.4c00365

Experimental method

X-RAY DIFFRACTION (3.02 Å)