Synthesis of aryl anilinomaleimide based derivatives as glycogen synthase kinase-3β inhibitors with potential role as antidepressant agents

2016 ◽  
Vol 40 (7) ◽  
pp. 6109-6119 ◽  
Author(s):  
Mushtaq A. Tantray ◽  
Imran Khan ◽  
Hinna Hamid ◽  
Mohammad Sarwar Alam ◽  
Abhijeet Dhulap ◽  
...  
Keyword(s):  
Animal Models ◽  
Potential Role ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Antidepressant Agents ◽  
Gsk 3Β

Novel anilinomaleimide based derivatives were found to inhibit GSK-3β activity in vitro and demonstrate anti-depressant effects in animal models.

scholarly journals Cyclic AMP Promotes Neuronal Survival by Phosphorylation of Glycogen Synthase Kinase 3β

2000 ◽  
Vol 20 (24) ◽  
pp. 9356-9363 ◽  
Author(s):  
Mingtao Li ◽  
Xiaomin Wang ◽  
Mary Kay Meintzer ◽  
Tracey Laessig ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Glycogen Synthase ◽  
Neuronal Survival ◽  
Glycogen Synthase Kinase ◽  
Intracellular Camp ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β ◽  
Camp Levels

ABSTRACT Agents that elevate intracellular cyclic AMP (cAMP) levels promote neuronal survival in a manner independent of neurotrophic factors. Inhibitors of phosphatidylinositol 3 kinase and dominant-inactive mutants of the protein kinase Akt do not block the survival effects of cAMP, suggesting that another signaling pathway is involved. In this report, we demonstrate that elevation of intracellular cAMP levels in rat cerebellar granule neurons leads to phosphorylation and inhibition of glycogen synthase kinase 3β (GSK-3β). The increased phosphorylation of GSK-3β by protein kinase A (PKA) occurs at serine 9, the same site phosphorylated by Akt. Purified PKA is able to phosphorylate recombinant GSK-3β in vitro. Inhibitors of GSK-3 block apoptosis in these neurons, and transfection of neurons with a GSK-3β mutant that cannot be phosphorylated interferes with the prosurvival effects of cAMP. These data suggest that activated PKA directly phosphorylates GSK-3β and inhibits its apoptotic activity in neurons.

scholarly journals Glycogen Synthase Kinase 3β Is Positively Regulated by Protein Kinase Cζ-Mediated Phosphorylation Induced by Wnt Agonists

2015 ◽  
Vol 36 (5) ◽  
pp. 731-741 ◽  
Author(s):  
Nydia Tejeda-Muñoz ◽  
Héctor González-Aguilar ◽  
Paula Santoyo-Ramos ◽  
M. Cristina Castañeda-Patlán ◽  
Martha Robles-Flores
Keyword(s):  
Protein Kinase ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Resting Cells ◽  
Malignant Cells ◽  
Glycogen Synthase Kinase 3Β ◽  
Colon Cells ◽  
Basal Activity ◽  
Gsk 3Β

The molecular events that drive Wnt-induced regulation of glycogen synthase kinase 3β (GSK-3β) activity are poorly defined. In this study, we found that protein kinase Cζ (PKCζ) and GSK-3β interact mainly in colon cancer cells. Wnt stimulation induced a rapid GSK-3β redistribution from the cytoplasm to the nuclei in malignant cells and a transient PKC-mediated phosphorylation of GSK-3β at a different site from serine 9. In addition, while Wnt treatment induced a decrease in PKC-mediated phosphorylation of GSK-3β in nonmalignant cells, in malignant cells, this phosphorylation was increased. Pharmacological inhibition and small interfering RNA (siRNA)-mediated silencing of PKCζ abolished all of these effects, but unexpectedly, it also abolished the constitutive basal activity of GSK-3β.In vitroactivity assays demonstrated that GSK-3β phosphorylation mediated by PKCζ enhanced GSK-3β activity. We mapped Ser147 of GSK-3β as the site phosphorylated by PKCζ, i.e., its mutation into alanine abolished GSK-3β activity, resulting in β-catenin stabilization and increased transcriptional activity, whereas phosphomimetic replacement of Ser147 by glutamic acid maintained GSK-3β basal activity. Thus, we found that PKCζ phosphorylates GSK-3β at Ser147 to maintain its constitutive activity in resting cells and that Wnt stimulation modifies the phosphorylation of Ser147 to regulate GSK-3β activity in opposite manners in normal and malignant colon cells.

scholarly journals Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinyang Li ◽  
Ji Gao ◽  
Haoming Zhou ◽  
Jinren Zhou ◽  
Zhenghua Deng ◽  
...  
Keyword(s):  
B Cells ◽  
Glycogen Synthase ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Novel Strategy ◽  
Gsk 3Β

CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.

Synthesis of benzimidazole-based 1,3,4-oxadiazole-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with antidepressant activity in in vivo models

RSC Advances ◽  
2016 ◽  
Vol 6 (49) ◽  
pp. 43345-43355 ◽  
Author(s):  
Mushtaq A. Tantray ◽  
Imran Khan ◽  
Hinna Hamid ◽  
Mohammad Sarwar Alam ◽  
Abhijeet Dhulap ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Antidepressant Activity ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
In Vivo Models ◽  
Gsk 3Β

Synthesized benzimidazole based 1,3,4-oxadiazole-1,2,3-triazole conjugates were found to inhibit GSK-3β activityin vitroand exhibit antidepressant-like activity inin vivostudies.

scholarly journals Characterization of the Interaction between Latency-Associated Nuclear Antigen and Glycogen Synthase Kinase 3β

2009 ◽  
Vol 83 (12) ◽  
pp. 6312-6317 ◽  
Author(s):  
Thilo Hagen
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Nuclear Antigen ◽  
Glycogen Synthase Kinase 3Β ◽  
Intact Cells ◽  
Von Hippel Lindau ◽  
Gsk 3Β ◽  
The Stability

ABSTRACT The latency-associated nuclear antigen (LANA) of Karposi's sarcoma-associated herpesvirus has been reported to interact with glycogen synthase kinase 3β (GSK-3β) and regulate its activity, leading to inhibition of GSK-3-dependent β-catenin degradation. In this study, the interaction between LANA and GSK-3β was characterized further. LANA was found to interact with GSK-3β in vitro as well as in intact cells. However, LANA did not regulate GSK-3β kinase activity and LANA-induced upregulation of β-catenin was GSK-3β independent. LANA did not regulate the stability of β-catenin or of its reported interaction partners p53 and von Hippel-Lindau protein. Additional targets of LANA are likely to mediate its malignancy-promoting function.

scholarly journals Contrasting Effects of Inhibitors Li+ and Be2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β

2021 ◽  
Author(s):  
David Reilley ◽  
Zaher Arraf ◽  
Anastassia N. Alexandrova
Keyword(s):  
Glycogen Synthase ◽  
Atomic Scale ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Therapeutic Window ◽  
Therapeutic Effects ◽  
Classical Dynamics ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

<div>Ionic lithium shows rare effectiveness for treating bipolar disorder and is a promising drug for treating neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks as a drug, mainly a narrow therapeutic window. Among the different targets of lithium, glycogen synthase kinase 3β (GSK-3β) might be the one responsible for its therapeutic effects. Developing alternative, selective inhibitors of this kinase could avoid lithium side effects, but efforts to do so have met little success so far. A detailed, atomistic understanding of Li+ inhibition and a more detailed understanding of the phosphorylation reaction GSK-3β catalyzes would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to fill out the atomic scale picture of Li+ GSK-3β inhibition. We compare Li+ action with Be2+, another known inhibitor, and find our results in agreement with in-vitro kinetics studies. Ultimately, our simulations show that Li+ inhibition is driven primarily by directly decreasing the reaction rate of the phosphorylation step, rather than reducing catalytic turnover through tight binding to different GSK-3β states like Be2+ inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg2+ and thus provides insight for the development of GSK-3β inhibitors based on other paradigms.</div>

scholarly journals Contrasting Effects of Inhibitors Li+ and Be2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β

2021 ◽  
Author(s):  
David Reilley ◽  
Zaher Arraf ◽  
Anastassia N. Alexandrova
Keyword(s):  
Glycogen Synthase ◽  
Atomic Scale ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Therapeutic Window ◽  
Therapeutic Effects ◽  
Classical Dynamics ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

<div>Ionic lithium shows rare effectiveness for treating bipolar disorder and is a promising drug for treating neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks as a drug, mainly a narrow therapeutic window. Among the different targets of lithium, glycogen synthase kinase 3β (GSK-3β) might be the one responsible for its therapeutic effects. Developing alternative, selective inhibitors of this kinase could avoid lithium side effects, but efforts to do so have met little success so far. A detailed, atomistic understanding of Li+ inhibition and a more detailed understanding of the phosphorylation reaction GSK-3β catalyzes would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to fill out the atomic scale picture of Li+ GSK-3β inhibition. We compare Li+ action with Be2+, another known inhibitor, and find our results in agreement with in-vitro kinetics studies. Ultimately, our simulations show that Li+ inhibition is driven primarily by directly decreasing the reaction rate of the phosphorylation step, rather than reducing catalytic turnover through tight binding to different GSK-3β states like Be2+ inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg2+ and thus provides insight for the development of GSK-3β inhibitors based on other paradigms.</div>

scholarly journals GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 610
Author(s):  
Robin Park ◽  
Andrew L. Coveler ◽  
Ludimila Cavalcante ◽  
Anwaar Saeed
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
In Vivo Models ◽  
Gsk 3Β ◽  
Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Microtubule-associated protein 1B phosphorylation by glycogen synthase kinase 3β is induced during PC12 cell differentiation

2001 ◽  
Vol 114 (23) ◽  
pp. 4273-4284 ◽  
Author(s):  
Robert G. Goold ◽  
Phillip R. Gordon-Weeks
Keyword(s):  
Cell Differentiation ◽  
Pc12 Cell ◽  
Glycogen Synthase ◽  
Axon Outgrowth ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Cell Extracts ◽  
Neurite Formation ◽  
Reduced Mobility

In recent studies we have demonstrated that glycogen synthase kinase 3β (GSK3β) and its substrate microtubule-associated protein 1B (MAP1B) regulate the microtubule cytoskeleton during axon outgrowth. To further examine the role GSK3β plays in axon outgrowth we investigated the expression of GSK3β and its activity towards MAP1B during nerve growth factor (NGF)-stimulated PC12 cell differentiation. Levels of GSK3β expression increase relatively little during the course of differentiation. However, the expression of a novel GSK3β isoform characterised by a reduced mobility on SDS gels is induced by NGF. Expression of this isoform and the GSK3β-phosphorylated isoform of MAP1B (MAP1B-P) are induced in parallel in response to NGF. This increase lags behind initial neurite formation and the expression of MAP1B in these cells by about two days and coincides with a period when the majority of cells are extending existing neurites. MAP1B and GSK3β are expressed throughout the PC12 cell but MAP1B-P expression is restricted to the growth cones and neurites. Consistent with these observations, we find that neurite extension is more sensitive to the GSK3 inhibitor Li+ than neurite formation and that this correlates with an inhibition of MAP1B phosphorylation. Additionally, GSK3β from PC12 cells not exposed to NGF can not phosphorylate MAP1B in vitro. However, a soluble factor in differentiated PC12 cell extracts depleted of GSK3β can activate MAP1B phosphorylation from undifferentiated cell extracts otherwise devoid of kinase activity. These experiments provide evidence for an NGF-mediated regulation of MAP1B phosphorylation in growing neurites by the induction of a novel isoform of GSK3β.

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