Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery?: Miniperspective
Open accessAbstract
Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown of different physiological networks. As result, several lines of evidence suggest that it could be more efficiently tackled by molecules directed toward different dysregulated biochemical targets or pathways. In this context, the selection of targets to which the new molecules will be directed is crucial. For years, the design of such multitarget-directed ligands (MTDLs) has been based on the selection of main targets involved in the "cholinergic" and the "β-amyloid" hypothesis. Recently, there have been some reports on MTDLs targeting the glycogen synthase kinase 3β (GSK-3β) enzyme, due to its appealing properties. Indeed, this enzyme is involved in tau hyperphosphorylation, controls a multitude of CNS-specific signaling pathways, and establishes strict connections with several factors implicated in AD pathogenesis. In the present Miniperspective, we will discuss the reasons behind the development of GSK-3β-directed MTDLs and highlight some of the recent efforts to obtain these new classes of MTDLs as potential disease-modifying agents.
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BACE-1 and GSK-3β inhibition are being studied as possible targets for Alzheimer's disease.
“Nowadays, other possible targets are being studied, such as beta-secretase 1 (BACE-1) and glycogen synthase kinase-3β (GSK-3β) inhibition (De Simone et al., 2021;Prati et al., 2015).”
From Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease (2022) · cites this paper as De Simone et al., 2021
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Cites
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases
MacDonald, B. T., Tamai, K., & He, X. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.06.016 · Cited by 5,583 · see citing works
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., & Binder, L. I. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.13.4913 · Cited by 3,676 · see citing works
SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE
DAVIES, P. (1976) · The Lancet · doi:10.1016/s0140-6736(76)91936-x · Cited by 3,565 · see citing works
Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) · Nature · doi:10.1038/31508 · Cited by 3,498 · see citing works
The amyloid state and its association with protein misfolding diseases.
Knowles, T. P. J., Vendruscolo, M., & Dobson, C. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3810 · Cited by 2,382 · see citing works
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease
Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., & Collin, F. (2018) · Redox Biology · doi:10.1016/j.redox.2017.10.014 · Cited by 2,185 · see citing works
GSK-3: tricks of the trade for a multi-tasking kinase
Doble, B. W., & Woodgett, J. R. (2003) · Journal of Cell Science · doi:10.1242/jcs.00384 · Cited by 2,084 · see citing works
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965 · see citing works
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954 · see citing works
Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases
Beurel, E., Grieco, S. F., & Jope, R. S. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.11.016 · Cited by 1,768 · see citing works
Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease
Ittner, L. M., & Götz, J. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2967 · Cited by 1,357 · see citing works
Designed Multiple Ligands. An Emerging Drug Discovery Paradigm
Morphy, R., & Ranković, Z. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058225d · Cited by 1,237 · see citing works
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Self-citationTau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113 · see citing works
Alzheimer's disease: strategies for disease modification
Citron, M. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd2896 · Cited by 1,060 · see citing works
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Alonso, A. D. C., Zaidi, T., Novák, M., Grundke, I., & Iqbal, K. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121119298 · Cited by 968 · see citing works
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Hanger, D. P., Anderton, B. H., & Noble, W. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.003 · Cited by 965 · see citing works
Alonso, A. D. C., Grundke-Iqbal, I., & Iqbal, K. (1996) · Nature Medicine · doi:10.1038/nm0796-783 · Cited by 859 · see citing works
Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease
Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1630428100 · Cited by 831 · see citing works
GSK3 signalling in neural development
Hur, E., & Zhou, F. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2870 · Cited by 828 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity
Huang, X., Cuajungco, M. P., Atwood, C. S., Hartshorn, M. A., Tyndall, J. D. A., Hanson, G. R., Stokes, K. C., Leopold, M., Multhaup, G., Goldstein, L. E., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37111 · Cited by 762 · see citing works
The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy
Sengupta, U., Nilson, A. N., & Kayed, R. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.03.035 · Cited by 740 · see citing works
Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J.-P., & Anderton, B. H. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90774-2 · Cited by 737 · see citing works
A perspective on multi‐target drug discovery and design for complex diseases
Ramsay, R. R., Popović-Nikolić, M. R., Nikolic, K. M., Uliassi, E., & Bolognesi, M. L. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-017-0181-2 · Cited by 730 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
Frame, S., Cohen, P., & Biondi, R. M. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00253-2 · Cited by 703 · see citing works
Alzheimer's disease drug development pipeline: 2018
Cummings, J., Lee, G., Ritter, A., & Zhong, K. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.03.009 · Cited by 697 · see citing works
Glycogen synthase kinase-3 signaling in Alzheimer's disease
Lauretti, E., Dincer, O., & Praticò, D. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118664 · Cited by 624 · see citing works
Matsuo, E. S., Shin, R., Billingsley, M., de Voorde, A. V., O'Connor, M., Trojanowski, J., & Lee, V. (1994) · Neuron · doi:10.1016/0896-6273(94)90264-x · Cited by 588 · see citing works
Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update
Roskoski, R. J. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104609 · Cited by 566 · see citing works
The road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565 · see citing works
Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E., & Mandelkow, E.-M. (1999) · Biochemistry · doi:10.1021/bi981874p · Cited by 564 · see citing works
Bhat, R. V., Xue, Y., von Berg, S., Hellberg, S., Ormö, M., Nilsson, Y., Radesäter, A., Jerning, E., Markgren, P.-O., Borgegård, T., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306268200 · Cited by 557 · see citing works
Alzheimer’s disease drug development pipeline: 2020
Cummings, J., Lee, G., Ritter, A., Sabbagh, M., & Zhong, K. (2020) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12050 · Cited by 557 · see citing works
A Phase II Trial of Tideglusib in Alzheimer's Disease
Lovestone, S., for the ARGO investigators, Boada, M., Dubois, B., Hüll, M., Rinne, J. O., Huppertz, H.-J., Calero, M., Andrés, M. V., Gómez-Carrillo, B., et al. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-141959 · Cited by 536 · see citing works
Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds
Proschak, E., Stark, H., & Merk, D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00760 · Cited by 498 · see citing works
Polypharmacology – Foe or Friend?
Peters, J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400856t · Cited by 477 · see citing works
Phosphorylation by Glycogen Synthase Kinase-3 Controls c-Myc Proteolysis and Subnuclear Localization
Gregory, M. A., Qi, Y., & Hann, S. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m310722200 · Cited by 476 · see citing works
Martı́nez, A., Alonso, M., Castro, A., Pérez, C., & Moreno, F. J. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm011020u · Cited by 457 · see citing works
Current understanding of metal ions in the pathogenesis of Alzheimer’s disease
Wang, L., Yin, Y.-L., Liu, X.-Z., Shen, P., Zheng, Y.-G., Lan, X.-R., Lu, C.-B., & Wang, J.-Z. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00189-z · Cited by 454 · see citing works
GSK-3β, a pivotal kinase in Alzheimer disease
Llorens-MarÃtin, M., Jurado, J., Hernández, F., & Ãvila, J. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00046 · Cited by 451 · see citing works
Porkka, K., Koskenvesa, P., Lundán, T., Rimpiläinen, J., Mustjoki, S., Smykla, R., Wild, R., Luo, R., Arnan, M., Brethon, B., et al. (2008) · Blood · doi:10.1182/blood-2008-02-140665 · Cited by 445 · see citing works
Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes
Ly, P. T. T., Wu, Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64516 · Cited by 442 · see citing works
Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies
Brunden, K. R., Trojanowski, J. Q., & Lee, V. M.-Y. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2959 · Cited by 440 · see citing works
CREB DNA binding activity is inhibited by glycogen synthase kinase‐3β and facilitated by lithium
Grimes, C. A., & Jope, R. S. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00495.x · Cited by 437 · see citing works
Chen, C.-H., Zhou, W., Liu, S., Deng, Y., Cai, F., Tone, M., Tone, Y., Tong, Y., & Song, W. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000149 · Cited by 433 · see citing works
Wen, P. Y., Yung, W. K. A., Lamborn, K. R., Dahia, P. L. M., Wang, Y., Peng, B., Abrey, L. E., Raizer, J. J., Cloughesy, T. F., Fink, K., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0773 · Cited by 424 · see citing works
GSK-3 and Wnt Signaling in Neurogenesis and Bipolar Disorder
Valvezan, A. J., & Klein, P. S. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00001 · Cited by 384 · see citing works
Paullones are potent inhibitors of glycogen synthase kinase‐3β and cyclin‐dependent kinase 5/p25
Leost, M., Schultz, C., Link, A., Wu, Y., Biernat, J., Mandelkow, E., Bibb, J. A., Snyder, G. L., Greengard, P., Zaharevitz, D. W., et al. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01673.x · Cited by 378 · see citing works
α-synuclein in the pathophysiology of Alzheimer’s disease
Twohig, D., & Nielsen, H. M. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0320-x · Cited by 374 · see citing works
Sengupta, A., Kabat, J., Novak, M., Wu, Q., Grundke-Iqbal, I., & Iqbal, K. (1998) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.0813 · Cited by 363 · see citing works
The amyloid hypothesis on trial
Makin, S. (2018) · Nature · doi:10.1038/d41586-018-05719-4 · Cited by 360 · see citing works
GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS
Eldar-Finkelman, H., & Martı́nez, A. (2011) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00032 · Cited by 356 · see citing works
Inflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Spangenberg, E. E., & Green, K. N. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.003 · Cited by 352 · see citing works
New Insights Into the Pathogenesis of Alzheimer's Disease
Fan, L., Mao, C., Hu, X., Zhang, S., Yang, Z., Hu, Z., Sun, H., Fan, Y., Dong, Y., Yang, J., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2019.01312 · Cited by 349 · see citing works
Glycogen synthase kinase‐3 inhibition is integral to long‐term potentiation
Hooper, C., Markevich, V. A., Plattner, F., Killick, R., Schofield, E., Engel, T., Hernández, F., Anderton, B. H., Rosenblum, K., Bliss, T., et al. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05245.x · Cited by 345 · see citing works
Forlenza, O. V., de Paula, V. D. J. R., & Diniz, B. S. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn5000309 · Cited by 333 · see citing works
Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study
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. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-120805 · Cited by 329 · see citing works
Bertrand, J. A., Thieffine, S., Vulpetti, A., Cristiani, C., Valsasina, B., Knapp, S., Kalisz, H. M., & Flocco, M. M. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.08.031 · Cited by 325 · see citing works
Lee, J. K., & Kim, N. (2017) · Molecules · doi:10.3390/molecules22081287 · Cited by 323 · see citing works
A phase 2 trial of the GSK‐3 inhibitor tideglusib in progressive supranuclear palsy
Tolosa, E., Litvan, I., Höglinger, G. U., Burn, D., Lees, A., Andrés, M. V., Gómez‐Carrillo, B., León, T., del Ser, T., & for the TAUROS Investigators (2014) · Movement Disorders · doi:10.1002/mds.25824 · Cited by 320 · see citing works
Naini, S. M. A., & Soussi‐Yanicostas, N. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/151979 · Cited by 318 · see citing works
Role of metal dyshomeostasis in Alzheimer's disease
Bonda, D., Lee, H., Blair, J. A., Zhu, X., Perry, G. L., & Smith, M. A. (2011) · Metallomics · doi:10.1039/c0mt00074d · Cited by 316 · see citing works
Tau pathophysiology in neurodegeneration: a tangled issue
Spires‐Jones, T. L., Stoothoff, W. H., de Calignon, A., Jones, P., & Hyman, B. T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2008.11.007 · Cited by 316 · see citing works
α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities
Alam, P., Bousset, L., Melki, R., & Otzen, D. E. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14808 · Cited by 305 · see citing works
Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice
Terwel, D., Muyllaert, D., Dewachter, I., Borghgraef, P., Croes, S., Devijver, H., & Van Leuven, F. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070904 · Cited by 300 · see citing works
Targeting protein kinases in central nervous system disorders
Chico, L. K., Eldik, L. J. V., & Watterson, D. M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2999 · Cited by 292 · see citing works
Targeting GSK3 and Associated Signaling Pathways Involved in Cancer
Duda, P., Akula, S. M., Abrams, S. L., Steelman, L. S., Martelli, A. M., Cocco, L., Ratti, S., Candido, S., Libra, M., Montalto, G., et al. (2020) · Cells · doi:10.3390/cells9051110 · Cited by 284 · see citing works
Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability
Alonso, A. D., Cohen, L. S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G., & Kleiman, F. E. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00338 · Cited by 278 · see citing works
Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux
Dai, H. I., Marbach, P., Lemaire, M., Hayes, M., & Elmquist, W. F. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.045260 · Cited by 274 · see citing works
Jicha, G. A., Lane, E., Vincent, I. J., Ötvös, L., Hoffmann, R., & Davies, P. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69052087.x · Cited by 264 · see citing works
Designing Multiple Ligands – Medicinal Chemistry Strategies and Challenges
Morphy, R., & Ranković, Z. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209787315594 · Cited by 262 · see citing works
Magdesian, M. H., Carvalho, M., Mendes, F. A., Saraiva, L. M., Juliano, M. A., Juliano, L., Garcia-Abreu, J., & Ferreira, S. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707108200 · Cited by 251 · see citing works
Rajasekhar, K., Chakrabarti, M., & Govindaraju, T. (2015) · Chemical Communications · doi:10.1039/c5cc05264e · Cited by 241 · see citing works
Selectivity and therapeutic inhibition of kinases: to be or not to be?
Ghoreschi, K., Laurence, A. D. J., & O’Shea, J. J. (2009) · Nature Immunology · doi:10.1038/ni.1701 · Cited by 241 · see citing works
Calcium signaling in Alzheimer's disease & therapies
Tong, B. C., Wu, A. J., Li, M., & Cheung, K. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.07.018 · Cited by 235 · see citing works
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
Emerging roles of <scp>ER</scp> stress in the etiology and pathogenesis of Alzheimer's disease
Gerakis, Y., & Hetz, C. (2018) · The FEBS Journal · doi:10.1111/febs.14332 · Cited by 226 · see citing works
Multi-target design strategies for the improved treatment of Alzheimer's disease
Zhang, P., Xu, S., Zhu, Z., & Xu, J. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.020 · Cited by 218 · see citing works
Targeting HDACs: A Promising Therapy for Alzheimer's Disease
Xu, K., Dai, X., Huang, H., & Jiang, Z.-F. (2011) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2011/143269 · Cited by 206 · see citing works
Regulation of protein stability by GSK3 mediated phosphorylation
Xu, C. B., Kim, N., & Gumbiner, B. M. (2009) · Cell Cycle · doi:10.4161/cc.8.24.10111 · Cited by 205 · see citing works
Glycogen Synthase Kinase 3β Functions To Specify Gene-Specific, NF-κB-Dependent Transcription
Steinbrecher, K. A., Wilson, W., Cogswell, P. C., & Baldwin, A. S. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.19.8444-8455.2005 · Cited by 205 · see citing works
Clinical use of lithium salts: guide for users and prescribers
for the International Group for Studies of Lithium (IGSLi), Tondo, L., Alda, M., Bauer, M., Bergink, V., Grof, P., Hájek, T., Lewitzka, U., Licht, R. W., Manchia, M., et al. (2019) · International Journal of Bipolar Disorders · doi:10.1186/s40345-019-0151-2 · Cited by 205 · see citing works
Fragments, network biology and designing multiple ligands
Morphy, R., & Ranković, Z. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.12.006 · Cited by 204 · see citing works
Protein-protein interaction modulators: advances, successes and remaining challenges
Mabonga, L., & Kappo, A. P. (2019) · Biophysical Reviews · doi:10.1007/s12551-019-00570-x · Cited by 196 · see citing works
Tau protein, the paired helical filament and Alzheimer's disease
Goedert, M., Klug, A., & Crowther, R. A. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s323 · Cited by 195 · see citing works
The Physicochemical Challenges of Designing Multiple Ligands
Morphy, R., & Ranković, Z. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm0603015 · Cited by 194 · see citing works
Sodium Oligomannate: First Approval
Syed, Y. Y. (2020) · Drugs · doi:10.1007/s40265-020-01268-1 · Cited by 187 · see citing works
Microdose Lithium Treatment Stabilized Cognitive Impairment in Patients with Alzheimer’s Disease
Nunes, M. A., Viel, T. A., & Buck, H. S. (2013) · Current Alzheimer Research · doi:10.2174/1567205011310010014 · Cited by 183 · see citing works
Inhibition of GSK3 by Wnt signalling – two contrasting models
Metcalfe, C., & Bienz, M. (2011) · Journal of Cell Science · doi:10.1242/jcs.091991 · Cited by 181 · see citing works
New Promise and Opportunities for Allosteric Kinase Inhibitors
Lu, X., Smaill, J. B., & Ding, K. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201914525 · Cited by 170 · see citing works
GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration
Salcedo‐Tello, P., Ortiz‐Matamoros, A., & Arias, C. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/189728 · Cited by 163 · see citing works
Targeting Fyn Kinase in Alzheimer’s Disease
Nygaard, H. B. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.06.004 · Cited by 162 · see citing works
GSK-3β at the Intersection of Neuronal Plasticity and Neurodegeneration
Jaworski, T., Banach, E., & Gralec, K. (2019) · Neural Plasticity · doi:10.1155/2019/4209475 · Cited by 161 · see citing works
Thal, D. R., Holzer, M., Rüb, U., Waldmann, G., Günzel, S., Zedlick, D., & Schober, R. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7380 · Cited by 160 · see citing works
Rhodanine‐Based Tau Aggregation Inhibitors in Cell Models of Tauopathy
Bulic, B., Pickhardt, M., Khlistunova, I., Biernat, J., Mandelkow, E., Mandelkow�, E., & Waldmann, H. (2007) · Angewandte Chemie International Edition · doi:10.1002/anie.200704051 · Cited by 158 · see citing works
Xavier, I. J., Mercier, P. A., McLoughlin, C., Ali, A., Woodgett, J. R., & Ovsenek, N. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002169200 · Cited by 155 · see citing works
GSK3 and Alzheimer’s disease: facts and fiction…
Kremer, A. (2011) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00017 · Cited by 155 · see citing works
GSK‐3: A key player in neurodegeneration and memory
Giese, K.-P. (2009) · IUBMB Life · doi:10.1002/iub.187 · Cited by 150 · see citing works
Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease
Cristóvão, J. S., Santos, R., & Gomes, C. M. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/9812178 · Cited by 146 · see citing works
Kramer, T., Schmidt, B., & Monte, F. L. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/381029 · Cited by 139 · see citing works
Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease
Magi, S., Castaldo, P., Macrì, M. L., Maiolino, M., Matteucci, A., Bastioli, G., Gratteri, S., Amoroso, S., & Lariccia, V. (2016) · BioMed Research International · doi:10.1155/2016/6701324 · Cited by 137 · see citing works
Prati, F., Bottegoni, G., Bolognesi, M. L., & Cavalli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00393 · Cited by 132 · see citing works
Harnessing Polypharmacology with Medicinal Chemistry
Bolognesi, M. L. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00039 · Cited by 129 · see citing works
Sivaprakasam, P., Han, X., Civiello, R. L., Jacutin-Porte, S., Kish, K., Pokross, M. E., Lewis, H. A., Ahmed, N., Szapiel, N., Newitt, J. A., et al. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.03.046 · Cited by 128 · see citing works
Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors
Prati, F., De Simone, A., Bisignano, P., Armirotti, A., Summa, M., Pizzirani, D., Scarpelli, R., Perez, D. I., Andrisano, V., Perez‐Castillo, A., et al. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201410456 · Cited by 128 · see citing works
Self-citationChen, P., Gu, Z., Liu, W., & Yan, Z. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.034942 · Cited by 128 · see citing works
Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies
Medina, M., Garrido, J. J., & Wandosell, F. G. (2011) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00024 · Cited by 124 · see citing works
Jiang, X.-Y., Chen, T.-K., Zhou, J.-T., He, S.-Y., Yang, H.-Y., Chen, Y., Qu, W., Feng, F., & Sun, H.-P. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00463 · Cited by 122 · see citing works
Henderson, B. W., Gentry, E. G., Rush, T., Troncoso, J. C., Thambisetty, M., Montine, T. J., & Herskowitz, J. H. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13688 · Cited by 120 · see citing works
Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease
Bulic, B., Pickhardt, M., & Mandelkow�, E. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm3017317 · Cited by 116 · see citing works
GSK-3 mediates the release of IL-1β, TNF-α and IL-10 from cortical glia
Green, H. F., & Nolan, Y. M. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.07.003 · Cited by 115 · see citing works
GSK3β Activity Modifies the Localization and Function of Presenilin 1
Uemura, K., Kuzuya, A., Shimozono, Y., Aoyagi, N., Andō, K., Shimohama, S., & Kinoshita, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610708200 · Cited by 114 · see citing works
Gandini, A., Bartolini, M., Tedesco, D., Martínez‐González, L., Roca, C., Campillo, N. E., Zaldívar-Díez, J., Pérez, C., Zuccheri, G., Miti, A., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00610 · Cited by 112 · see citing works
Present Algorithms and Future Treatments for Alzheimer’s Disease
Grossberg, G. T., Tong, G., Burke, A. D., & Tariot, P. N. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180903 · Cited by 109 · see citing works
Palomo, V., Soteras, I., Pérez, D. I., Pérez, C., Gil, C., Campillo, N. E., & Martı́nez, A. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200996g · Cited by 108 · see citing works
Kozikowski, A. P., Gaisina, I. N., Petukhov, P. A., Sridhar, J., King, L. T., Blond, S. Y., Duka, T., Rusnak, M., & Sidhu, A. (2006) · ChemMedChem · doi:10.1002/cmdc.200500039 · Cited by 103 · see citing works
Wagner, F. F., Benajiba, L., Campbell, A. J., Weïwer, M., Sacher, J. R., Gale, J. P., Ross, L. S., Puissant, A., Alexe, G., Conway, A. S., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aam8460 · Cited by 100 · see citing works
TIA1 regulates the generation and response to toxic tau oligomers
Jiang, L., Ash, P. E. A., Maziuk, B. F., Ballance, H. I., Boudeau, S., Abdullatif, A. A., Orlando, M., Petrucelli, L., Ikezu, T., & Wolozin, B. L. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1937-5 · Cited by 99 · see citing works
Lee, S. J., Chung, Y. H., Joo, K. M., Lim, H. C., Jeon, G. S., Kim, D., Lee, W. B., Kim, Y. S., & Ik, C. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.09.026 · Cited by 96 · see citing works
New Insights in Amyloid Beta Interactions with Human Telomerase
Wang, J., Zhao, C., Zhao, A., Li, M., Ren, J., & Qu, X. (2015) · Journal of the American Chemical Society · doi:10.1021/ja511030s · Cited by 90 · see citing works
Horrigan, J. P., Gomes, T. M. B., Snape, M., Nikolenko, N., McMorn, A., Evans, S., Yaroshinsky, A., Pasqua, O. E. D., Oosterholt, S. P., & Lochmüller, H. (2020) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2020.08.001 · Cited by 89 · see citing works
Evidence for a new binding mode to GSK-3: Allosteric regulation by the marine compound palinurin
Bidon‐Chanal, A., Fuertes, A., Alonso, D. A., Pérez, D. I., Martı́nez, A., Luque, F. J., & Medina, M. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.12.014 · Cited by 73 · see citing works
Simone, A. D., & Milelli, A. (2019) · ChemMedChem · doi:10.1002/cmdc.201900174 · Cited by 72 · see citing works
Self-citationInestrosa, N., Alvarez, A. R., & Calderón, F. H. (1996) · PubMed · Cited by 71 · see citing works
Xu, M., Wang, S. L., Zhu, L., Wu, P., Dai, W., & Rakesh, K. P. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.12.073 · Cited by 71 · see citing works
BACE inhibitor bust in Alzheimer trial
Mullard, A. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.43 · Cited by 70 · see citing works
Prati, F., Simone, A. D., Armirotti, A., Summa, M., Pizzirani, D., Scarpelli, R., Bertozzi, S. M., Pérez, D. I., Andrisano, V., Pérez‐Castillo, A., et al. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00121 · Cited by 68 · see citing works
Self-citationOukoloff, K., Coquelle, N., Bartolini, M., Naldi, M., Guével, R. L., Bach, S., Josselin, B., Ruchaud, S., Catto, M., Pisani, L., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.12.063 · Cited by 66 · see citing works
The role of GSK3beta in the development of the central nervous system
Luo, J. (2012) · Frontiers in Biology · doi:10.1007/s11515-012-1222-2 · Cited by 65 · see citing works
Hui, J., Zhang, J., Pu, M., Zhou, X., Dong, L., Mao, X., Shi, G., Zou, J., Wu, J., Jiang, D., et al. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy040 · Cited by 60 · see citing works
Simone, A. D., Pietra, V. L., Betari, N., Petragnani, N., Conte, M., Daniele, S., Pietrobono, D., Martini, C., Petralla, S., Casadei, R., et al. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00507 · Cited by 58 · see citing works
Self-citationShi, X., Wu, J., Liu, P., & Liu, Z. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.02.001 · Cited by 55 · see citing works
Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold
Wang, C. K. L., Northfield, S. E., Huang, Y., Ramos, M. C., & Craik, D. J. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.01.006 · Cited by 52 · see citing works
Tacrine-based Multifunctional Agents in Alzheimer's Disease: An Old Story in Continuous Development§
Milelli, A., Simone, A. D., Ticchi, N., et al. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170309123920 · Cited by 52 · see citing works
Self-citationArfeen, M., Bhagat, S., Patel, R. V., et al. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.04.075 · Cited by 49 · see citing works
Brogi, S., Ramunno, A., Savi, L., Chemi, G., Alfano, G., Pecorelli, A., Pambianchi, E., Galatello, P., Compagnoni, G., Focher, F., et al. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.06.017 · Cited by 45 · see citing works
Cost of Treatment and Care for People with Alzheimer’s Disease: A Meta- Analysis
Marešová, P., Dolejš, J., Mohelská, H., & Bryan, L. L. K. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200102144640 · Cited by 45 · see citing works
Ballatore, C., Brunden, K. R., Trojanowski, J. Q., Lee, V. M. Y., Smith, A. B., & Huryn, D. M. (2010) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611794072605 · Cited by 44 · see citing works
Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease
Jaworski, T., Kügler, S., & LEUVEN, F. V. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/573138 · Cited by 42 · see citing works
DAPK1: a Novel Pathology and Treatment Target for Alzheimer’s Disease
Xu, L.-Z., Li, B.-Q., & Jia, J.-P. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1242-2 · Cited by 42 · see citing works
Hansen, L., Arden, K. C., Rasmussen, S., Viars, C. S., Vestergaard, H., Hansen, T. F., Møller, A. M., Woodgett, J. R., & Pedersen, O. B. (1997) · Diabetologia · doi:10.1007/s001250050771 · Cited by 39 · see citing works
Boulahjar, R., Ouach, A., Bourg, S., Bonnet, P., Lozach, O., Meijer, L., Guguen‐Guillouzo, C., Guével, R. L., Lazar, S., Mohamed Akssira, A., et al. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.06.046 · Cited by 35 · see citing works
Glycogen synthase kinase‐3 and alternative splicing
Liu, X., & Klein, P. S. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1501 · Cited by 35 · see citing works
Butini, S., Gemma, S., Brindisi, M., Borrelli, G., Lossani, A., Ponte, A. M., Torti, A., Maga, G., Marinelli, L., Pietra, V. L., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101438u · Cited by 30 · see citing works
Zhang, P., Li, S., Gao, Y., Lu, W., Huang, K., Ye, D., Li, X., & Chu, Y. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.10.078 · Cited by 30 · see citing works
Recent Advances in Designing Substrate-Competitive Protein Kinase Inhibitors
Han, K.-C., Kim, S. Y., & Yang, E. G. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212800672697 · Cited by 14 · see citing works
“It Ain’t Over ’til It’s Over”a—The Search for Treatments and Cures for Alzheimer’s Disease
Hargreaves, R. J. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300359g · Cited by 14 · see citing works
Modulation of tau pathology in tau transgenic models
Brion, J., Ando, K., Héraud, C., & Leroy, K. (2010) · Biochemical Society Transactions · doi:10.1042/bst0380996 · Cited by 11 · see citing works
Savi, L., Brindisi, M., Alfano, G., et al. (2015) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12630 · Cited by 7 · see citing works
Glycogen Synthase Kinase-3 Beta
National Cancer Institute (2020) · Definitions · doi:10.32388/84ie1d · Cited by 7 · see citing works
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Challenges and hopes for Alzheimer’s disease
Tatulian, S. A. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.01.016 · Cited by 291 · see citing works
Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease
Fernandes, F., Barroso, M. F., De Simone, A., Emriková, E., Dias-Teixeira, M., Pereira, J. P., Chlebek, J., Fernandes, V. C., Rodrigues, F., Andrisano, V., et al. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115107 · Cited by 45 · see citing works
Self-citationDong, Y., Lu, J., Zhang, S., Chen, L., Wen, J., Wang, F., Mao, Y., Li, L., Zhang, J., Liao, S., et al. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106446 · Cited by 28 · see citing works
Coulon, A., Rabiller, F., Takalo, M., Roy, A., Pelletier, A., Martiskainen, H., Siedlecki-Wullich, D., Lannette-Weimann, N., Majerníková, N., Grenon, A., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02709-5 · Cited by 1 · see citing works
- Authors
- De Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A.
- Affiliations
- Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Torino, Italy
- University of Bologna (IT)
- Corresponding author
- Milelli, Andrea
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-21
- Volume
- 64
- Issue
- 1
- Pages
- 26-41
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC8016207
- OpenAlex
- W3113759919
- Cited by
- 110
- References
- 156
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 19 · 2023: 15 · 2022: 22 · 2021: 7
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Universit? di Bologna
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- glycogen synthase kinase-3β, multi-target-directed ligands, Alzheimer's disease, tau hyperphosphorylation, disease-modifying drugs, GSK-3β inhibitors, cholinergic hypothesis, amyloid hypothesis
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Humans, Phosphorylation, Drug Discovery
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