{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:51:07Z","timestamp":1790898667430,"version":"4.1.0"},"reference-count":110,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T00:00:00Z","timestamp":1681862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3\u03b2 is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3\u03b2 and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3\u03b2, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3\u03b2 inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3\u03b2 in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3\u03b2 inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.<\/jats:p>","DOI":"10.3390\/ijms24087541","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T03:25:11Z","timestamp":1681961111000},"page":"7541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["GSK-3\u03b2 Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-4235","authenticated-orcid":false,"given":"Beatrice","family":"Balboni","sequence":"first","affiliation":[{"name":"Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0919-5206","authenticated-orcid":false,"given":"Mirco","family":"Masi","sequence":"additional","affiliation":[{"name":"Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Rocchia","sequence":"additional","affiliation":[{"name":"Computational mOdelling of NanosCalE and bioPhysical sysTems (CONCEPT) Lab, Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16152 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-6675","authenticated-orcid":false,"given":"Stefania","family":"Girotto","sequence":"additional","affiliation":[{"name":"Structural Biophysics and Translational Pharmacology Facility, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6370-1176","authenticated-orcid":false,"given":"Andrea","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Computational and Chemical Biology, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/bs.ctdb.2016.11.011","article-title":"Glycogen Synthase Kinase 3: A Kinase for All Pathways?","volume":"123","author":"Patel","year":"2017","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/S0092-8674(01)00374-9","article-title":"Crystal Structure of Glycogen Synthase Kinase 3\u03b2: Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition","volume":"105","author":"Dajani","year":"2001","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1159\/000485580","article-title":"The Key Roles of GSK-3\u03b2 in Regulating Mitochondrial Activity","volume":"44","author":"Yang","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen Synthase Kinase-3 (GSK3): Regulation, Actions, and Diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.2174\/138161211797052484","article-title":"The Possible Involvement of Glycogen Synthase Kinase-3 (GSK-3) in Diabetes, Cancer and Central Nervous System Diseases","volume":"17","author":"Amar","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_6","first-page":"1761","article-title":"Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications","volume":"35","author":"Muneer","year":"2017","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_7","first-page":"822","article-title":"Deficiency in the Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3 Increases Sensitivity to Mood Disturbances","volume":"14","author":"Polter","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1111\/bdi.12023","article-title":"Glycogen Synthase Kinase-3 Levels and Phosphorylation Undergo Large Fluctuations in Mouse Brain during Development","volume":"14","author":"Beurel","year":"2012","journal-title":"Bipolar Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1111\/j.1471-4159.2007.05194.x","article-title":"The GSK3 Hypothesis of Alzheimer\u2019s Disease","volume":"104","author":"Hooper","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_10","first-page":"46","article-title":"GSK-3\u03b2, a pivotal kinase in Alzheimer disease","volume":"7","author":"Jurado","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.3892\/mmr.2014.2080","article-title":"Association of glycogen synthase kinase-3\u03b2 with Parkinson\u2019s disease (review)","volume":"9","author":"Li","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/cdd.2014.179","article-title":"GSK-3\u03b2 Dysregulation Contributes to Parkinson\u2019s-like Pathophysiology with Associated Region-Specific Phosphorylation and Accumulation of Tau and \u03b1-Synuclein","volume":"22","author":"Credle","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.phrs.2015.03.010","article-title":"Glycogen synthase kinase-3 beta (GSK-3\u03b2) signaling: Implications for Parkinson\u2019s disease","volume":"97","author":"Golpich","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1093\/hmg\/ddu119","article-title":"Localized Changes to Glycogen Synthase Kinase-3 and Collapsin Response Mediator Protein-2 in the Huntington\u2019s Disease Affected Brain","volume":"23","author":"Lim","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2206","DOI":"10.1038\/cddis.2016.104","article-title":"GSK-3\u03b2-Induced Tau Pathology Drives Hippocampal Neuronal Cell Death in Huntington\u2019s Disease: Involvement of Astrocyte-Neuron Interactions","volume":"7","author":"Tirolo","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5040","DOI":"10.1093\/hmg\/ddv224","article-title":"Decreased Glycogen Synthase Kinase-3 Levels and Activity Contribute to Huntington\u2019s Disease","volume":"24","author":"Miguez","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4061\/2011\/189246","article-title":"GSK-3 in Neurodegenerative Diseases","volume":"2011","author":"Lei","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.semcancer.2017.12.010","article-title":"Glycogen Synthase Kinases: Moonlighting Proteins with Theranostic Potential in Cancer","volume":"56","author":"Nagini","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1097\/IGC.0b013e31820d7366","article-title":"Overexpression of Glycogen Synthase Kinase-3 in Ovarian Carcinoma Cells with Acquired Paclitaxel Resistance","volume":"21","author":"Fu","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.bbrc.2012.05.147","article-title":"GSK-3 Inhibition in Vitro and in Vivo Enhances Antitumor Effect of Sorafenib in Renal Cell Carcinoma (RCC)","volume":"423","author":"Kawazoe","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1038\/s41467-018-07644-6","article-title":"GSK3 Suppression Upregulates \u03b2-Catenin and c-Myc to Abrogate KRas-Dependent Tumors","volume":"9","author":"Kazi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/4629495","article-title":"Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases","volume":"2017","author":"Mancinelli","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.18632\/oncotarget.2037","article-title":"GSK-3 as Potential Target for Therapeutic Irvention in Cancer","volume":"5","author":"Mccubrey","year":"2014","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Domoto, T., Uehara, M., Bolidong, D., and Minamoto, T. (2020). Glycogen Synthase Kinase 3\u03b2 in Cancer Biology and Treatment. Cells, 9.","DOI":"10.3390\/cells9061388"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Masi, M., Racchi, M., Travelli, C., Corsini, E., and Buoso, E. (2021). Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers. Cells, 10.","DOI":"10.3390\/cells10112999"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/mc.10087","article-title":"Expression, Localization, and Activity of Glycogen Synthase Kinase 3\u03b2 during Mouse Skin Tumorigenesis","volume":"35","author":"Leis","year":"2002","journal-title":"Mol. Carcinog."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1038\/onc.2014.279","article-title":"Effect of Glycogen Synthase Kinase-3 Inactivation on Mouse Mammary Gland Development and Oncogenesis","volume":"34","author":"Dembowy","year":"2015","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1111\/j.1349-7006.2007.00545.x","article-title":"Inhibition of GSK-3\u03b2 Activity Attenuates Proliferation of Human Colon Cancer Cells in Rodents","volume":"98","author":"Shakoori","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2174\/156800907780618266","article-title":"Glycogen Synthase Kinase-3 Beta; A New Target in Pancreatic Cancer?","volume":"7","author":"Garcea","year":"2007","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10066","DOI":"10.1021\/jm401466v","article-title":"Design, Synthesis, and Biological Evaluation of 1-Phenylpyrazolo[3,4-e]Pyrrolo[3,4-G]Indolizine-4,6(1 H,5 h)-Diones as New Glycogen Synthase Kinase-3\u03b2 Inhibitors","volume":"56","author":"Coluccia","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.ejmech.2016.04.075","article-title":"Design, Synthesis and Biological Evaluation of 5-Benzylidene-2-Iminothiazolidin-4-Ones as Selective GSK-3\u03b2 Inhibitors","volume":"121","author":"Arfeen","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1016\/j.bmc.2009.05.031","article-title":"Synthesis and Biological Evaluation of Novel 4-Azaindolyl-Indolyl-Maleimides as Glycogen Synthase Kinase-3\u03b2 (GSK-3\u03b2) Inhibitors","volume":"17","author":"Ye","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"C1289","DOI":"10.1152\/ajpcell.00061.2019","article-title":"Identification of a Novel Selective and Potent Inhibitor of Glycogen Synthase Kinase-3","volume":"317","author":"Noori","year":"2019","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ejmech.2016.09.058","article-title":"Natural and synthetic bioactive inhibitors of glycogen synthase kinase","volume":"125","author":"Khan","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3389\/fnmol.2017.00391","article-title":"Saijilafu Differential Roles of Glycogen Synthase Kinase 3 Subtypes Alpha and Beta in Cortical Development","volume":"10","author":"Ma","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1080\/13543776.2020.1815706","article-title":"Glycogen Synthase Kinase 3 (GSK-3) Inhibitors: A Patent Update (2016\u20132019)","volume":"30","author":"Roca","year":"2020","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8461","DOI":"10.1021\/jm200996g","article-title":"Exploring the Binding Sites of Glycogen Synthase Kinase 3. Identification and Characterization of Allosteric Modulation Cavities","volume":"54","author":"Palomo","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1021\/acscentsci.7b00211","article-title":"Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis","volume":"3","author":"Decherchi","year":"2017","journal-title":"ACS Cent. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Decherchi, S., and Rocchia, W. (2013). A General and Robust Ray-Casting-Based Algorithm for Triangulating Surfaces at the Nanoscale. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059744"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/bioinformatics\/bty761","article-title":"NanoShaper\u2013VMD Interface: Computing and Visualizing Surfaces, Pockets and Channels in Molecular Systems","volume":"35","author":"Decherchi","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_41","unstructured":"Gagliardi, L., and Rocchia, W. (2022). SiteFerret: Beyond Simple Pocket Identification in Proteins. arXiv."},{"key":"ref_42","unstructured":"Alonso Gordillo, D., Dorronsoro Diaz, I., Martinez Gil, A., Panizo del Pliego, G., Fuertes Huerta, A., Perez Puerto, M.J., Martin Aparicio, E., Perez Navarro, D., and Medina Padilla, M. (2005). GSK-3 Inhibitors Isolated from Marine Organisms. (WO2005054221A1), U.S. Patent."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.jalz.2006.05.2076","article-title":"P4\u2013335: Glycogen Synthase Kinase\u20133\u03b2 Inhibitors from Marine Origin","volume":"2","author":"Alonso","year":"2006","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_44","first-page":"32","article-title":"GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS","volume":"4","author":"Martinez","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_45","first-page":"3252","article-title":"The First Enantioselective Synthesis of Palinurin","volume":"22","author":"Castro","year":"2009","journal-title":"Chem. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.ejmech.2010.12.024","article-title":"An Application of Two MIFs-Based Tools (Volsurf+ and Pentacle) to Binary QSAR: The Case of a Palinurin-Related Data Set of Non-ATP Competitive Glycogen Synthase Kinase 3\u03b2 (GSK-3\u03b2) Inhibitors","volume":"46","author":"Ermondi","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.ejmech.2012.12.014","article-title":"Evidence for a New Binding Mode to GSK-3: Allosteric Regulation by the Marine Compound Palinurin","volume":"60","author":"Fuertes","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/prot.1159","article-title":"Classical Molecular Interaction Potentials: Improved Setup Procedure in Molecular Dynamics Simulations of Proteins","volume":"45","author":"Kalko","year":"2001","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6404","DOI":"10.1021\/ja00280a055","article-title":"Manzamine A, a Novel Antitumor Alkaloid from a Sponge","volume":"108","author":"Sakai","year":"1986","journal-title":"J. Am. Chem. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1021\/jm030475b","article-title":"New Manzamine Alkaloids from an Indo-Pacific Sponge. Pharmacokinetics, Oral Availability, and the Significant Activity of Several Manzamines against HIV-I, AIDS Opportunistic Infections, and Inflammatory Diseases","volume":"47","author":"Yousaf","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1021\/np0601399","article-title":"Manzamine B and E and Ircinal A Related Alkaloids from an Indonesian Acanthostrongylophora Sponge and Their Activity against Infectious, Tropical Parasitic, and Alzheimer\u2019s Diseases","volume":"69","author":"Rao","year":"2006","journal-title":"J. Nat. Prod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1021\/np060092r","article-title":"Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure-Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer\u2019s Disease","volume":"70","author":"Hamann","year":"2007","journal-title":"J. Nat. Prod."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lin, L.-C., Kuo, T.-T., Chang, H.-Y., Liu, W.-S., Hsia, S.-M., and Huang, T.-C. (2018). Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells. Mar. Drugs, 16.","DOI":"10.3390\/md16080252"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s10637-010-9422-6","article-title":"A Novel Activity from an Old Compound: Manzamine A Reduces the Metastatic Potential of AsPC-1 Pancreatic Cancer Cells and Sensitizes Them to TRAIL-Induced Apoptosis","volume":"29","author":"Johnson","year":"2011","journal-title":"Investig. New Drugs"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Mamaghani, S., Simpson, C.D., Cao, P.M., Cheung, M., Chow, S., Bandarchi, B., Schimmer, A.D., and Hedley, D.W. (2012). Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to TRAIL-Induced Apoptosis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041102"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1021\/jm900672t","article-title":"Structure\u2014Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections","volume":"53","author":"Peng","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1007\/s11172-010-0344-4","article-title":"Interaction of Manzamine A with Glycogen Synthase Kinase 3\u03b2: A Molecular Dynamics Study","volume":"59","author":"Osolodkin","year":"2010","journal-title":"Russ. Chem. Bull."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1021\/jm011020u","article-title":"First Non-ATP Competitive Glycogen Synthase Kinase 3 \u03b2 (GSK-3\u03b2) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer\u2019s Disease","volume":"45","author":"Martinez","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1016\/S0968-0896(97)00077-1","article-title":"Arylimino-1,2,4-Thiadiazolidinones: A New Family of Potassium Channel Openers","volume":"5","author":"Castro","year":"1997","journal-title":"Bioorg. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0223-5234(00)01166-1","article-title":"N-Benzylpiperidine Derivatives of 1,2,4-Thiadiazolidinone as New Acetylcholinesterase Inhibitors","volume":"35","author":"Martinez","year":"2000","journal-title":"Eur. J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/syn.20839","article-title":"Genetic and Pharmacological Evidence for Schizophrenia-Related Disc1 Interaction with GSK-3","volume":"65","author":"Lipina","year":"2011","journal-title":"Synapse"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1073\/pnas.0307921101","article-title":"Lithium Antagonizes Dopamine-Dependent Behaviors Mediated by an AKT\/Glycogen Synthase Kinase 3 Signaling Cascade","volume":"101","author":"Beaulieu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/cns.12683","article-title":"GSK-3\u03b2 Inhibitor TDZD-8 Reduces Neonatal Hypoxic-Ischemic Brain Injury in Mice","volume":"23","author":"Huang","year":"2017","journal-title":"CNS Neurosci Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1158\/1078-0432.CCR-04-2624","article-title":"Activation of P53-Dependent Apoptosis by Acute Ablation of Glycogen Synthase Kinase-3\u03b2 in Colorectal Cancer Cells","volume":"11","author":"Ghosh","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1182\/blood-2007-05-088815","article-title":"Rapid and Selective Death of Leukemia Stem and Progenitor Cells Induced by the Compound 4-Benzyl, 2-Methyl, 1,2,4-Thiadiazolidine, 3,5 Dione (TDZD-8)","volume":"110","author":"Guzman","year":"2007","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Aguilar-Morante, D., Morales-Garcia, J.A., Sanz-Sancristobal, M., Garcia-Cabezas, M.A., Santos, A., and Perez-Castillo, A. (2010). Inhibition of Glioblastoma Growth by the Thiadiazolidinone Compound TDZD-8. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013879"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1002\/pros.21300","article-title":"Suppression of Glycogen Synthase Kinase 3 Activity Reduces Tumor Growth of Prostate Cancer in Vivo","volume":"71","author":"Zhu","year":"2011","journal-title":"Prostate"},{"key":"ref_68","first-page":"1159","article-title":"Clinicopathological and Biological Significance of Aberrant Activation of Glycogen Synthase Kinase-3 in Ovarian Cancer","volume":"7","author":"Fu","year":"2014","journal-title":"Onco Targets Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1096\/fj.04-1551fje","article-title":"Glycogen Synthase Kinase 3\u03b2 (GSK3\u03b2) Mediates 6- Hydroxydopamine-induced Neuronal Death","volume":"18","author":"Chen","year":"2004","journal-title":"FASEB J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23527","DOI":"10.1038\/srep23527","article-title":"Inhibition of Glycogen Synthase Kinase-3\u03b2 (GSK-3\u03b2) as Potent Therapeutic Strategy to Ameliorates L-Dopa-Induced Dyskinesia in 6-OHDA Parkinsonian Rats","volume":"6","author":"Xie","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neuint.2018.10.022","article-title":"The GSK3\u03b2 Inhibitor, TDZD-8, Rescues Cognition in a Zebrafish Model of Okadaic Acid-Induced Alzheimer\u2019s Disease","volume":"122","author":"Koehler","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/abbs\/gmaa002","article-title":"Inhibition of Glycogen Synthase Kinase 3\u03b2 Improves Cognitive Function in Aged Mice by Upregulating Claudin Presences in Cerebral Endothelial Cells","volume":"52","author":"Liang","year":"2021","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1096\/fj.08-120410","article-title":"A-Synuclein Contributes to GSK-3\u03b2-catalyzed Tau Phosphorylation in Parkinson\u2019s Disease Models","volume":"23","author":"Duka","year":"2009","journal-title":"FASEB J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kerr, F., Sofola-Adesakin, O., Ivanov, D.K., Gatliff, J., Gomez Perez-Nievas, B., Bertrand, H.C., Martinez, P., Callard, R., Snoeren, I., and Cochem\u00e9, H.M. (2017). Direct Keap1-Nrf2 Disruption as a Potential Therapeutic Target for Alzheimer\u2019s Disease. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006593"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.neurobiolaging.2017.05.010","article-title":"Glucocorticoid-Mediated Activation of GSK3\u03b2 Promotes Tau Phosphorylation and Impairs Memory in Type 2 Diabetes","volume":"57","author":"Dey","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.12659\/MSM.897739","article-title":"Inhibition of GSK-3\u03b2 Alleviates Collagen II-Induced Rheumatoid Arthritis in Rats","volume":"22","author":"Zhou","year":"2016","journal-title":"Med. Sci. Monit."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000471808","article-title":"Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice","volume":"101","author":"Mateus","year":"2017","journal-title":"Pharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.nbd.2009.05.025","article-title":"A Novel GSK-3\u03b2 Inhibitor Reduces Alzheimer\u2019s Pathology and Rescues Neuronal Loss In Vivo","volume":"35","author":"Coma","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1074\/jbc.M111.306472","article-title":"Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3\u03b2 by Tideglusib","volume":"287","author":"Fuertes","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3233\/JAD-141959","article-title":"A Phase II Trial of Tideglusib in Alzheimer\u2019s Disease","volume":"45","author":"Lovestone","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_81","first-page":"205","article-title":"Treatment of Alzheimer\u2019s Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study","volume":"33","author":"Steinwachs","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/mds.25815","article-title":"Tideglusib Reduces Progression of Brain Atrophy in Progressive Supranuclear Palsy in a Randomized Trial","volume":"29","author":"Huppertz","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/mds.25824","article-title":"A Phase 2 Trial of the GSK-3 Inhibitor Tideglusib in Progressive Supranuclear Palsy","volume":"29","author":"Tolosa","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"391","DOI":"10.6026\/97320630012391","article-title":"Pharmacophore Feature-Based Virtual Screening for Finding Potent GSK-3 Inhibitors Using Molecular Docking and Dynamics Simulations","volume":"12","author":"Chauhan","year":"2016","journal-title":"Bioinformation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.1021\/jm034108b","article-title":"Thienyl and Phenyl \u03b1-Halomethyl Ketones: New Inhibitors of Glycogen Synthase Kinase (GSK-3\u03b2) from a Library of Compound Searching","volume":"46","author":"Conde","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"6914","DOI":"10.1016\/j.bmc.2009.08.042","article-title":"Thienylhalomethylketones: Irreversible Glycogen Synthase Kinase 3 Inhibitors as Useful Pharmacological Tools","volume":"17","author":"Perez","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1021\/jm1016279","article-title":"Switching Reversibility to Irreversibility in Glycogen Synthase Kinase 3 Inhibitors: Clues for Specific Design of New Compounds","volume":"54","author":"Perez","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1021\/jm201463v","article-title":"5-Imino-1,2,4-Thiadiazoles: First Small Molecules As Substrate Competitive Inhibitors of Glycogen Synthase Kinase 3","volume":"55","author":"Palomo","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"srep43545","DOI":"10.1038\/srep43545","article-title":"Promoting in Vivo Remyelination with Small Molecules: A Neuroreparative Pharmacological Treatment for Multiple Sclerosis","volume":"7","author":"Boyd","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13024-018-0251-y","article-title":"Modulation of GSK-3 Provides Cellular and Functional Neuroprotection in the Rd10 Mouse Model of Retinitis Pigmentosa","volume":"13","author":"Marchena","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Ben\u00edtez-Fern\u00e1ndez, R., Melero-Jerez, C., Gil, C., de la Rosa, E.J., Mart\u00ednez, A., and de Castro, F. (2021). Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052440"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/978-3-030-27378-1_72","article-title":"GSK-3 Inhibitors: From the Brain to the Retina and Back Again","volume":"1185","year":"2019","journal-title":"In Adv. Exp. Med. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7232","DOI":"10.1016\/j.bmcl.2012.09.043","article-title":"Identification of Novel Scaffold of Benzothiazepinones as Non-ATP Competitive Glycogen Synthase Kinase-3\u03b2 Inhibitors through Virtual Screening","volume":"22","author":"Zhang","year":"2012","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ejmech.2012.09.021","article-title":"Design, Synthesis and Biological Evaluation of Benzothiazepinones (BTZs) as Novel Non-ATP Competitive Inhibitors of Glycogen Synthase Kinase-3\u03b2 (GSK-3\u03b2)","volume":"61","author":"Zhang","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5639","DOI":"10.1016\/j.bmcl.2014.10.078","article-title":"Novel Benzothiazinones (BTOs) as Allosteric Modulator or Substrate Competitive Inhibitor of Glycogen Synthase Kinase 3\u03b2 (GSK-3\u03b2) with Cellular Activity of Promoting Glucose Uptake","volume":"24","author":"Zhang","year":"2014","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.ejmech.2017.04.039","article-title":"The Discovery of Novel Benzothiazinones as Highly Selective Non-ATP Competitive Glycogen Synthase Kinase 3\u03b2 Inhibitors for the Treatment of Ovarian Cancer","volume":"135","author":"Gao","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/sj.cr.7310078","article-title":"Glycogen Synthase Kinase-3\u03b2 Positively Regulates the Proliferation of Human Ovarian Cancer Cells","volume":"16","author":"Cao","year":"2006","journal-title":"Cell Res"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Rico, A., Guembelzu, G., Palomo, V., Mart\u00ednez, A., Aiastui, A., Casas-fraile, L., Valls, A., de Munain, A.L., and S\u00e1enz, A. (2021). Allosteric Modulation of GSK-3\u03b2 as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-related. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147367"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5000","DOI":"10.4049\/jimmunol.1203057","article-title":"Regulation of Th1 Cells and Experimental Autoimmune Encephalomyelitis by Glycogen Synthase Kinase-3","volume":"190","author":"Beurel","year":"2013","journal-title":"J. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4983","DOI":"10.1021\/acs.jmedchem.7b00395","article-title":"Subtly Modulating Glycogen Synthase Kinase 3 \u03b2: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases","volume":"60","author":"Palomo","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e202200663","DOI":"10.1002\/cmdc.202200663","article-title":"Front Cover: Synthesis of Unsymmetrical Squaramides as Allosteric GSK-3\u03b2 Inhibitors Promoting \u0392-Catenin-Mediated Transcription of TCF\/LEF in Retinal Pigment Epithelial Cells","volume":"17","author":"Carullo","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Silva, G.M., Borges, R.S., Santos, K.L.B., Federico, L.B., Francischini, I.A.G., Gomes, S.Q., Barcelos, M.P., Silva, R.C., Santos, C.B.R., and Silva, C.H.T.P. (2021). Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3\u03b2 Allosteric Modulators Addressed to Neurodegenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158252"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Rippin, I., Khazanov, N., Shirley Ben Joseph Kudinov, T., Berent, E., Arciniegas Ruiz, S.M., Marciano, D., Levy, L., Gruzman, A., Senderowitz, H., and Eldar-Finkelman, H. (2020). Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228709"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jmb.2011.02.036","article-title":"Elucidating Substrate and Inhibitor Binding Sites on the Surface of GSK-3\u03b2 and the Refinement of a Competitive Inhibitor","volume":"408","author":"Plotkin","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_105","first-page":"ra110","article-title":"A Unique Type of GSK-3 Inhibitor Brings New Opportunities to the Clinic","volume":"9","author":"Paz","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1210\/jc.2012-4085","article-title":"Clinical review: Kinase inhibitors: Adverse effects related to the endocrine system","volume":"98","author":"Lodish","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_107","first-page":"922","article-title":"Structure- and Similarity-Based Survey of Allosteric Kinase Inhibitors, Activators, and Closely Related Compounds","volume":"65","author":"Hu","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Balboni, B., Tripathi, S.K., Veronesi, M., Russo, D., Penna, I., Giabbai, B., Bandiera, T., Storici, P., Girotto, S., and Cavalli, A. (2022). Identification of Novel GSK-3\u03b2 Hits Using Competitive Biophysical Assays. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073856"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1021\/acsmedchemlett.0c00563","article-title":"Fragment-Based Discovery of Novel Allosteric MEK1 Binders","volume":"12","author":"Edfeldt","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_110","first-page":"43","article-title":"Classifying Druggability on Potential Binding Sites of Glycogen Synthase Kinase-3\u03b2: An in-Silico Assessment","volume":"55","author":"Chauhan","year":"2017","journal-title":"Acta Pharm. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:19:15Z","timestamp":1760123955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,19]]},"references-count":110,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087541"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087541","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,19]]}}}