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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors

Author(s): Pankaj Wadhwa, Priti Jain and Hemant R. Jadhav*

Volume 20, Issue 17, 2020

Page: [1522 - 1534] Pages: 13

DOI: 10.2174/1568026620666200516153136

Price: $65


Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer’s disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer’s disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer’s disease.

Keywords: Glycogen Synthase Kinase 3, Alzheimer`s disease, Cancer, Inflammation, Inhibitors, Tideglusib.

Graphical Abstract
Martín, M.L.; Jurado, J.; Hernández, F.; Avila, J. GSK-3β, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci., 2014, 7(46), 1-11.
Maurer, U.; Preiss, F.; Brauns-Schubert, P.; Schlicher, L.; Charvet, C. GSK-3 - at the crossroads of cell death and survival. J. Cell Sci., 2014, 127(Pt 7), 1369-1378.
[] [PMID: 24687186]
Woodgett, J.R. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J., 1990, 9(8), 2431-2438.
[] [PMID: 2164470]
Lau, K.F.; Miller, C.C.J.; Anderton, B.H.; Shaw, P.C. Expression analysis of glycogen synthase kinase-3 in human tissues. J. Pept. Res., 1999, 54(1), 85-91.
[] [PMID: 10448973]
Agam, G.; Bersudsky, Y.; Berry, G.T.; Moechars, D.; Lavi-Avnon, Y.; Belmaker, R.H. Knockout mice in understanding the mechanism of action of lithium. Biochem. Soc. Trans., 2009, 37(Pt 5), 1121-1125.
[] [PMID: 19754464]
Petit-Paitel, A. [GSK-3beta: a central kinase for neurodegenerative diseases?]. Med. Sci. (Paris), 2010, 26(5), 516-521.
[] [PMID: 20510151]
Mancinelli, R.; Carpino, G.; Petrungaro, S.; Mammola, C.L.; Tomaipitinca, L.; Filippini, A.; Facchiano, A.; Ziparo, E.; Giampietri, C. Multifaceted roles of GSK-3 in cancer and autophagy-related diseases. Oxid. Med. Cell. Longev., 2017, 2017, 4629495.
[] [PMID: 29379583]
Lal, H.; Ahmad, F.; Woodgett, J.; Force, T. The GSK-3 family as therapeutic target for myocardial diseases. Circ. Res., 2015, 116(1), 138-149.
[] [PMID: 25552693]
Lee, H.C.; Tsai, J.N.; Liao, P.Y.; Tsai, W.Y.; Lin, K.Y.; Chuang, C.C.; Sun, C.K.; Chang, W.C.; Tsai, H.J. Glycogen synthase kinase 3 α and 3 β have distinct functions during cardiogenesis of zebrafish embryo. BMC Dev. Biol., 2007, 7(1), 93.
[] [PMID: 17683539]
Medunjanin, S.; Schleithoff, L.; Fiegehenn, C.; Weinert, S.; Zuschratter, W.; Braun-Dullaeus, R.C. GSK-3β controls NF kappaB activity via IKKγ/NEMO. Sci. Rep., 2016, 6, 38553.
[] [PMID: 27929056]
Kerkela, R.; Kockeritz, L.; Macaulay, K.; Zhou, J.; Doble, B.W.; Beahm, C.; Greytak, S.; Woulfe, K.; Trivedi, C.M.; Woodgett, J.R.; Epstein, J.A.; Force, T.; Huggins, G.S. Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. J. Clin. Invest., 2008, 118(11), 3609-3618.
[] [PMID: 18830417]
Hardt, S.E.; Sadoshima, J. Glycogen synthase kinase-3β: a novel regulator of cardiac hypertrophy and development. Circ. Res., 2002, 90(10), 1055-1063.
[] [PMID: 12039794]
Frame, S.; Cohen, P.; Biondi, R.M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell, 2001, 7(6), 1321-1327.
[] [PMID: 11430833]
Cohen, P.; Frame, S. The renaissance of GSK3. Nat. Rev. Mol. Cell Biol., 2001, 2(10), 769-776.
[] [PMID: 11584304]
Beurel, E.; Grieco, S.F.; Jope, R.S. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther., 2015, 148, 114-131.
[] [PMID: 25435019]
Uemura, K.; Kuzuya, A.; Shimozono, Y.; Aoyagi, N.; Ando, K.; Shimohama, S.; Kinoshita, A. GSK3beta activity modifies the localization and function of presenilin 1. J. Biol. Chem., 2007, 282(21), 15823-15832.
[] [PMID: 17389597]
Wu, D.; Pan, W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem. Sci., 2010, 35(3), 161-168.
[] [PMID: 19884009]
Caspi, M.; Zilberberg, A.; Eldar-Finkelman, H.; Rosin-Arbesfeld, R. Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner. Oncogene, 2008, 27(25), 3546-3555.
[] [PMID: 18223684]
Bechard, M.; Dalton, S. Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal. Mol. Cell. Biol., 2009, 29(8), 2092-2104.
[] [PMID: 19223464]
Shin, S.H.; Lee, E.J.; Chun, J.; Hyun, S.; Kim, Y.I.; Kang, S.S. The nuclear localization of glycogen synthase kinase 3β is required its putative PY-nuclear localization sequences. Mol. Cells, 2012, 34(4), 375-382.
[] [PMID: 23104438]
Jain, P.; Wadhwa, P.K.; Jadhav, H.R. Reactive Astrogliosis: Role in Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets, 2015, 14(7), 872-879.
[] [PMID: 26166438]
Pei, J.J.; Tanaka, T.; Tung, Y.C.; Braak, E.; Iqbal, K.; Grundke-Iqbal, I. Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J. Neuropathol. Exp. Neurol., 1997, 56(1), 70-78.
[] [PMID: 8990130]
Hye, A.; Riddoch-Contreras, J.; Baird, A.L.; Ashton, N.J.; Bazenet, C.; Leung, R.; Westman, E.; Simmons, A.; Dobson, R.; Sattlecker, M.; Lupton, M.; Lunnon, K.; Keohane, A.; Ward, M.; Pike, I.; Zucht, H.D.; Pepin, D.; Zheng, W.; Tunnicliffe, A.; Richardson, J.; Gauthier, S.; Soininen, H.; Kłoszewska, I.; Mecocci, P.; Tsolaki, M.; Vellas, B.; Lovestone, S. Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement., 2014, 10(6), 799-807.e2.
[] [PMID: 25012867]
Abiola, M.; Favier, M.; Christodoulou-Vafeiadou, E.; Pichard, A.L.; Martelly, I.; Guillet-Deniau, I. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS One, 2009, 4(12), e8509.
[] [PMID: 20041157]
Tejeda-Muñoz, N.; Robles-Flores, M. Glycogen synthase kinase 3 in Wnt signaling pathway and cancer. IUBMB Life, 2015, 67(12), 914-922.
[] [PMID: 26600003]
Wang, Y.; Hao, Y.; Alway, S.E. Suppression of GSK-3β activation by M-cadherin protects myoblasts against mitochondria-associated apoptosis during myogenic differentiation. J. Cell Sci., 2011, 124(Pt 22), 3835-3847.
[] [PMID: 22114306]
Dolma, K.; Iacobucci, G.J.; Hong Zheng, K.; Shandilya, J.; Toska, E.; White, J.A., II; Spina, E.; Gunawardena, S. Presenilin influences glycogen synthase kinase-3 β (GSK-3β) for kinesin-1 and dynein function during axonal transport. Hum. Mol. Genet., 2014, 23(5), 1121-1133.
[] [PMID: 24105467]
Twomey, C.; McCarthy, J.V. Presenilin-1 is an unprimed glycogen synthase kinase-3beta substrate. FEBS Lett., 2006, 580(17), 4015-4020.
[] [PMID: 16814287]
Chen, L.; Hou, J.; Fu, X.; Chen, X.; Wu, J.; Han, X. tPA promotes the proliferation of lung fibroblasts and activates the Wnt/β-catenin signaling pathway in idiopathic pulmonary fibrosis. Cell Cycle, 2019, 18(22), 3137-3146.
[] [PMID: 31550972]
Kremer, A.; Louis, J.V.; Jaworski, T.; Van Leuven, F. GSK3 and Alzheimer’s disease: facts and fiction. Front. Mol. Neurosci., 2011, 4, 17.
[] [PMID: 21904524]
Wang, Y.; Tian, Q.; Liu, E.J.; Zhao, L.; Song, J.; Liu, X.A.; Ren, Q.G.; Jiang, X.; Zeng, J.; Yang, Y.T.; Wang, J.Z. Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats. J. Cell. Mol. Med., 2017, 21(12), 3515-3528.
[] [PMID: 28656644]
Wang, H.; Wang, R.; Zhao, Z.; Ji, Z.; Xu, S.; Holscher, C.; Sheng, S. Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. Brain Res., 2009, 1249, 237-243.
[] [PMID: 19013138]
Kowaltowski, A.J.; Castilho, R.F.; Vercesi, A.E. Mitochondrial permeability transition and oxidative stress. FEBS Lett., 2001, 495(1-2), 12-15.
[] [PMID: 11322939]
Song, Y.; Brady, S.T. Stabilization of neuronal connections and the axonal cytoskeleton. Bioarchitecture, 2014, 4(1), 22-24.
[] [PMID: 24492417]
Garrido, J.J.; Simón, D.; Varea, O.; Wandosell, F. GSK3 alpha and GSK3 beta are necessary for axon formation. FEBS Lett., 2007, 581(8), 1579-1586.
[] [PMID: 17391670]
Kokubo, H.; Kayed, R.; Glabe, C.G.; Yamaguchi, H. Soluble Abeta oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer’s disease brain. Brain Res., 2005, 1031(2), 222-228.
[] [PMID: 15649447]
Sergeant, N.; Bretteville, A.; Hamdane, M.; Caillet-Boudin, M.L.; Grognet, P.; Bombois, S.; Blum, D.; Delacourte, A.; Pasquier, F.; Vanmechelen, E.; Schraen-Maschke, S.; Buée, L. Biochemistry of Tau in Alzheimer’s disease and related neurological disorders. Expert Rev. Proteomics, 2008, 5(2), 207-224.
[] [PMID: 18466052]
Hooper, C.; Markevich, V.; Plattner, F.; Killick, R.; Schofield, E.; Engel, T.; Hernandez, F.; Anderton, B.; Rosenblum, K.; Bliss, T.; Cooke, S.F.; Avila, J.; Lucas, J.J.; Giese, K.P.; Stephenson, J.; Lovestone, S. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur. J. Neurosci., 2007, 25(1), 81-86.
[] [PMID: 17241269]
Cuesto, G.; Jordán-Álvarez, S.; Enriquez-Barreto, L.; Ferrús, A.; Morales, M.; Acebes, Á. GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons. PLoS One, 2015, 10(3)e0118475
[] [PMID: 25764078]
Bach, J.H.; Chae, H.S.; Rah, J.C.; Lee, M.W.; Park, C.H.; Choi, S.H.; Choi, J.K.; Lee, S.H.; Kim, Y.S.; Kim, K.Y.; Lee, W.B.; Suh, Y.H.; Kim, S.S. C-terminal fragment of amyloid precursor protein induces astrocytosis. J. Neurochem., 2001, 78(1), 109-120.
[] [PMID: 11432978]
Jope, R.S.; Yuskaitis, C.J.; Beurel, E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem. Res., 2007, 32(4-5), 577-595.
[] [PMID: 16944320]
Walz, A.; Ugolkov, A.; Chandra, S.; Kozikowski, A.; Carneiro, B.A.; O’Halloran, T.V.; Giles, F.J.; Billadeau, D.D.; Mazar, A.P. Molecular pathways: revisiting glycogen synthase kinase-3β as a target for the treatment of cancer. Clin. Cancer Res., 2017, 23(8), 1891-1897.
[] [PMID: 28053024]
Xia, Y.; Shen, S.; Verma, I.M. NF-κB, an active player in human cancers. Cancer Immunol. Res., 2014, 2(9), 823-830.
[] [PMID: 25187272]
Peineau, S.; Bradley, C.; Taghibiglou, C.; Doherty, A.; Bortolotto, Z.A.; Wang, Y.T.; Collingridge, G.L. The role of GSK-3 in synaptic plasticity. Br. J. Pharmacol., 2008, 153(Suppl. 1), S428-S437.
[] [PMID: 18311157]
Venter, J.; Perez, C.; van Otterlo, W.A.L.; Martínez, A.; Blackie, M.A.L. 1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2019, 29(13), 1597-1600.
[] [PMID: 31054862]
Kim, W.H.; Jeong, P.; Kim, S.W.; Cho, H.; Lee, J.M.; Seo, S.; Shen, H.; Ahn, Y.; Jung, D.W.; Kim, Y.C.; Williams, D.R. Chemical characterization and biological activity data for a novel indirubin derivative, LDD-1819. Data Brief, 2019, 25, 104373.
[] [PMID: 31489353]
Li, Z.; Zhu, H.; Liu, C.; Wang, Y.; Wang, D.; Liu, H.; Cao, W.; Hu, Y.; Lin, Q.; Tong, C.; Lu, M.; Sachinidis, A.; Li, L.; Peng, L. GSK-3β inhibition protects the rat heart from the lipopolysaccharide induced inflammation injury via suppressing FOXO3A activity. J. Cell. Mol. Med., 2019, 23(11), 7796-7809.
[] [PMID: 31503410]
Paudel, P.; Seong, S.H.; Zhou, Y.; Ha, M.T.; Min, B.S.; Jung, H.A.; Choi, J.S. Arylbenzofurans from the root bark of morus alba as triple inhibitors of cholinesterase, β-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase-3β: relevance to alzheimer’s disease. ACS Omega, 2019, 4(4), 6283-6294.
[] [PMID: 31459768]
Zhou, Y.; Zhang, L.; Fu, X.; Jiang, Z.; Tong, R.; Shi, J.; Li, J.; Zhong, L. Design, synthesis and in vitro tumor cytotoxicity evaluation of 3,5-diamino-n-substituted benzamide derivatives as novel gsk-3β small molecule inhibitors. Chem. Biodivers., 2019, 16(9), e1900304.
[] [PMID: 31338947]
Hulcová, D.; Maříková, J.; Korábečný, J.; Hošťálková, A.; Jun, D.; Kuneš, J.; Chlebek, J.; Opletal, L.; De Simone, A.; Nováková, L.; Andrisano, V.; Růžička, A.; Cahlíková, L. Amaryllidaceae alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master as potential drugs in treatment of Alzheimer’s disease. Phytochemistry, 2019, 165, 112055.
[] [PMID: 31261031]
Andreev, S.; Pantsar, T.; Ansideri, F.; Kudolo, M.; Forster, M.; Schollmeyer, D.; Laufer, S.A.; Koch, P. Design, synthesis and biological evaluation of 7-chloro-9h-pyrimido[4,5-b]indole-based glycogen synthase kinase-3β inhibitors. Molecules, 2019, 24(12), 2331.
[] [PMID: 31242571]
Paudel, P.; Seong, S.H.; Zhou, Y.; Park, C.H.; Yokozawa, T.; Jung, H.A.; Choi, J.S. Rosmarinic acid derivatives’ inhibition of glycogen synthase kinase-3β is the pharmacological basis of kangen-karyu in alzheimer’s disease. Molecules, 2018, 23(11), E2919.
[] [PMID: 30413117]
Liang, Z.; Li, Q.X. Discovery of selective, substrate-competitive, and passive membrane permeable glycogen synthase kinase-3β inhibitors: synthesis, biological evaluation, and molecular modeling of new c-glycosylflavones. ACS Chem. Neurosci., 2018, 9(5), 1166-1183.
[] [PMID: 29381861]
Kumar, A.; Srivastava, G.; Negi, A.S.; Sharma, A. Docking, molecular dynamics, binding energy-MM-PBSA studies of naphthofuran derivatives to identify potential dual inhibitors against BACE-1 and GSK-3β. J. Biomol. Struct. Dyn., 2019, 37(2), 275-290.
[] [PMID: 29310523]
Vallée, A.; Lecarpentier, Y.; Guillevin, R.; Vallée, J-N. Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim. Biophys. Sin. (Shanghai), 2017, 49(10), 853-866.
[] [PMID: 28981597]
Gameiro, I.; Michalska, P.; Tenti, G.; Cores, Á.; Buendia, I.; Rojo, A.I.; Georgakopoulos, N.D.; Hernández-Guijo, J.M.; Teresa Ramos, M.; Wells, G.; López, M.G.; Cuadrado, A.; Menéndez, J.C.; León, R. Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease. Sci. Rep., 2017, 7, 45701.
[] [PMID: 28361919]
Wu, X.; Kosaraju, J.; Tam, K.Y. SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tauhyperphosphorylation via down-regulating GSK-3β activity in SHSY5Y cells. Eur. J. Pharm. Sci., 2017, 110, 101-108.
[] [PMID: 28359686]
Joshi, P.; Gupta, M.; Vishwakarma, R.A.; Kumar, A.; Bharate, S.B. (Z)-2-(3-Chlorobenzylidene)-3,4-dihydro-N-(2-methoxyethyl)-3- oxo-2H-benzo[b][1,4]oxazine-6-carboxamide as GSK-3β inhibitor: Identification by virtual screening and its validation in enzyme- and cell-based assay. Chem. Biol. Drug Des., 2017, 89(6), 964-971.
[] [PMID: 27896926]
Kim, J.; Moon, Y.; Hong, S. Identification of lead small molecule inhibitors of glycogen synthase kinase-3 beta using a fragment linking strategy. Bioorg. Med. Chem. Lett., 2016, 26(23), 5669-5673.
[] [PMID: 27815120]
Liang, S.H.; Chen, J.M.; Normandin, M.D.; Chang, J.S.; Chang, G.C.; Taylor, C.K.; Trapa, P.; Plummer, M.S.; Para, K.S.; Conn, E.L.; Lopresti-Morrow, L.; Lanyon, L.F.; Cook, J.M.; Richter, K.E.; Nolan, C.E.; Schachter, J.B.; Janat, F.; Che, Y.; Shanmugasundaram, V.; Lefker, B.A.; Enerson, B.E.; Livni, E.; Wang, L.; Guehl, N.J.; Patnaik, D.; Wagner, F.F.; Perlis, R.; Holson, E.B.; Haggarty, S.J.; El Fakhri, G.; Kurumbail, R.G.; Vasdev, N. Discovery of a highly selective glycogen synthase kinase-3 inhibitor (pf-04802367) that modulates tau phosphorylation in the brain: translation for pet neuroimaging. Angew. Chem. Int. Ed. Engl., 2016, 55(33), 9601-9605.
[] [PMID: 27355874]
Nisha, C.M.; Kumar, A.; Vimal, A.; Bai, B.M.; Pal, D.; Kumar, A. Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor. J. Mol. Graph. Model., 2016, 65, 100-107.
[] [PMID: 26967552]
Ombrato, R.; Cazzolla, N.; Mancini, F.; Mangano, G. Structure based discovery of 1h-indazole-3-carboxamides as a novel structural class of human gsk-3 inhibitors. J. Chem. Inf. Model., 2015, 55(12), 2540-2551.
[] [PMID: 26600430]
Dago, C.D.; Ambeu, C.N.; Coulibaly, W.K.; Békro, Y.A.; Mamyrbékova, J.; Defontaine, A.; Baratte, B.; Bach, S.; Ruchaud, S.; Guével, R.L.; Ravache, M.; Corlu, A.; Bazureau, J.P. Synthetic Development of New 3-(4-Arylmethylamino)butyl-5-arylidenerhodanines under Microwave Irradiation and Their Effects on Tumor Cell Lines and against Protein Kinases. Molecules, 2015, 20(7), 12412-12435.
[] [PMID: 26184130]
Lu, J.; Maezawa, I.; Weerasekara, S.; Erenler, R.; Nguyen, T.D.T.; Nguyen, J.; Swisher, L.Z.; Li, J.; Jin, L-W.; Ranjan, A.; Srivastava, S.K.; Hua, D.H. Syntheses, neural protective activities, and inhibition of glycogen synthase kinase-3β of substituted quinolines. Bioorg. Med. Chem. Lett., 2014, 24(15), 3392-3397.
[] [PMID: 24951331]
Park, S.M.; Ki, S.H.; Han, N.R.; Cho, I.J.; Ku, S.K.; Kim, S.C.; Zhao, R.J.; Kim, Y.W. Tacrine, an oral acetylcholinesterase inhibitor, induced hepatic oxidative damage, which was blocked by liquiritigenin through GSK3-beta inhibition. Biol. Pharm. Bull., 2015, 38(2), 184-192.
[] [PMID: 25747977]
Lovestone, S.; Boada, M.; Dubois, B.; Hüll, M.; Rinne, J.O.; Huppertz, H.J.; Calero, M.; Andrés, M.V.; Gómez-Carrillo, B.; León, T.; del Ser, T. ARGO investigators. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis., 2015, 45(1), 75-88.
[] [PMID: 25537011]
Waiker, D.K.; Karthikeyan, C.; Poongavanam, V.; Kongsted, J.; Lozach, O.; Meijer, L.; Trivedi, P. Synthesis, biological evaluation and molecular modelling studies of 4-anilinoquinazoline derivatives as protein kinase inhibitors. Bioorg. Med. Chem., 2014, 22(6), 1909-1915.
[] [PMID: 24530227]
Yoshida, J.; Seino, H.; Ito, Y.; Nakano, T.; Satoh, T.; Ogane, Y.; Suwa, S.; Koshino, H.; Kimura, K. Inhibition of glycogen synthase kinase-3β by falcarindiol isolated from Japanese Parsley (Oenanthe javanica). J. Agric. Food Chem., 2013, 61(31), 7515-7521.
[] [PMID: 23895038]
Georgievska, B.; Sandin, J.; Doherty, J.; Mörtberg, A.; Neelissen, J.; Andersson, A.; Gruber, S.; Nilsson, Y.; Schött, P.; Arvidsson, P.I.; Hellberg, S.; Osswald, G.; Berg, S.; Fälting, J.; Bhat, R.V. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J. Neurochem., 2013, 125(3), 446-456.
[] [PMID: 23410232]
Hu, S.; Cui, W.; Mak, S.; Tang, J.; Choi, C.; Pang, Y.; Han, Y. Bis(propyl)-cognitin protects against glutamate-induced neuroexcitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3β pathways. Neurochem. Int., 2013, 62(4), 468-477.
[] [PMID: 23357479]
Tell, V.; Holzer, M.; Herrmann, L.; Mahmoud, K.A.; Schächtele, C.; Totzke, F.; Hilgeroth, A. Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9- oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases. Bioorg. Med. Chem. Lett., 2012, 22(22), 6914-6918.
[] [PMID: 23039927]
Lo Monte, F.; Kramer, T.; Gu, J.; Brodrecht, M.; Pilakowski, J.; Fuertes, A.; Dominguez, J.M.; Plotkin, B.; Eldar-Finkelman, H.; Schmidt, B. Structure-based optimization of oxadiazole-based GSK-3 inhibitors. Eur. J. Med. Chem., 2013, 61, 26-40.
[] [PMID: 22749643]
Onishi, T.; Iwashita, H.; Uno, Y.; Kunitomo, J.; Saitoh, M.; Kimura, E.; Fujita, H.; Uchiyama, N.; Kori, M.; Takizawa, M. A novel glycogen synthase kinase‐3 inhibitor 2‐methyl‐5‐(3‐4‐[(S)‐methylsulfinyl] phenyl‐1‐benzofuran‐5‐yl)‐1, 3, 4‐oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer’s disease. J. Neurochem., 2011, 119(6), 1330-1340.
[] [PMID: 21992552]
Saitoh, M.; Kunitomo, J.; Kimura, E.; Yamano, T.; Itoh, F.; Kori, M. Enantioselective synthesis of the novel chiral sulfoxide derivative as a glycogen synthase kinase 3β inhibitor. Chem. Pharm. Bull. (Tokyo), 2010, 58(9), 1252-1254.
[] [PMID: 20823611]
Zhong, H.; Zou, H.; Semenov, M.V.; Moshinsky, D.; He, X.; Huang, H.; Li, S.; Quan, J.; Yang, Z.; Lin, S. Characterization and development of novel small-molecules inhibiting GSK3 and activating Wnt signaling. Mol. Biosyst., 2009, 5(11), 1356-1360.
[] [PMID: 19823752]
Beauchard, A.; Laborie, H.; Rouillard, H.; Lozach, O.; Ferandin, Y.; Le Guével, R.; Guguen-Guillouzo, C.; Meijer, L.; Besson, T.; Thiéry, V. Synthesis and kinase inhibitory activity of novel substituted indigoids. Bioorg. Med. Chem., 2009, 17(17), 6257-6263.
[] [PMID: 19665384]
Khanfar, M.A.; Asal, B.A.; Mudit, M.; Kaddoumi, A.; El Sayed, K.A. The marine natural-derived inhibitors of glycogen synthase kinase-3β phenylmethylene hydantoins: In vitro and in vivo activities and pharmacophore modeling. Bioorg. Med. Chem., 2009, 17(16), 6032-6039.
[] [PMID: 19616957]
Serenó, L.; Coma, M.; Rodríguez, M.; Sánchez-Ferrer, P.; Sánchez, M.B.; Gich, I.; Agulló, J.M.; Pérez, M.; Avila, J.; Guardia-Laguarta, C.; Clarimón, J.; Lleó, A.; Gómez-Isla, T. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol. Dis., 2009, 35(3), 359-367.
[] [PMID: 19523516]
Morales-Garcia, J.A.; Luna-Medina, R.; Alonso-Gil, S.; Sanz-Sancristobal, M.; Palomo, V.; Gil, C.; Santos, A.; Martinez, A.; Perez-Castillo, A. Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chem. Neurosci., 2012, 3(11), 963-971.
[] [PMID: 23173075]
Wang, H.; Huang, S.; Yan, K.; Fang, X.; Abussaud, A.; Martinez, A.; Sun, H.S.; Feng, Z.P. Tideglusib, a chemical inhibitor of GSK3β, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim. Biophys. Acta, 2016, 1860(10), 2076-2085.
[] [PMID: 27378458]
del Ser, T.; Steinwachs, K.C.; Gertz, H.J.; Andrés, M.V.; Gómez-Carrillo, B.; Medina, M.; Vericat, J.A.; Redondo, P.; Fleet, D.; León, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimers Dis., 2013, 33(1), 205-215.
[] [PMID: 22936007]
Hampel, H.; Ewers, M.; Bürger, K.; Annas, P.; Mörtberg, A.; Bogstedt, A.; Frölich, L.; Schröder, J.; Schönknecht, P.; Riepe, M.W.; Kraft, I.; Gasser, T.; Leyhe, T.; Möller, H.J.; Kurz, A.; Basun, H. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry, 2009, 70(6), 922-931.
[] [PMID: 19573486]

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