生物活性

• 靶点

  GSK-3β IC50:5nM

  GSK-3β (C199A) IC50:60nM

• 描述GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase, consisting of GSK-3 and subunit, which plays a key role in many different biological processes including tumorigenesis, cell survival, and developmental patterning. GSK-3 is constitutively active in non-stimulated cells and can negatively regulate canonical Wnt/-catenin signaling^[2][3]. Tideglusib is a thiadiazolidinedione-derived GSK-3 inhibitor with Ki value of 60nM (calculated by double ATP and inhibitor titrations) and can inhibit GSK-3 with IC50 value of 105nM (measured by enzymatic assays of human recombinant GSK-3)^[1]. Tideglusib can increase the level of phosphorylated GSK3-S9, as well as decreased the level of phosphorylated tau, in a dose or time dependent manner in GSC11 cells treated on dose of 0-10uM or in 0-6h^[4]. Tideglusib shows neuroprotection against hypoxic-ischemic brain injury in neonatal mice. Intraperitoneal administration of tideglusib (5 mg/kg) 20 min prior to the onset of ischemia can reduce cerebral infarct volume at both 24 h and 7 days after hypoxic-ischemic injury^[5]. Several clinical studies on neurological diseases, including two phase 2 studies of Alzheimer's disease, have been completed (see in https://www.clinicaltrials.gov/).
• 作用机制Tideglusib is a thiadiazolidinedione-derived non-ATP competitive inhibitor of GSK3.

• 动物研究
  剂量	Mice: min = 50 mg/kg[7], max = 200 mg/kg p.o.[8]; 5 mg/kg i.p.[5]
  给药途径	p.o., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01049399	Progressive Supranuclear Palsy	Not Applicable	Completed	-	United States, California ... more >> The Parkinson's and Movement Disorder Institute Fountain Valley, California, United States, 92708 Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California, United States, 90095 United States, Florida Mayo Clinic Jacksonville Jacksonville, Florida, United States, 32224 University of South Florida 5 Tampa, Florida, United States, 33606 United States, Kentucky Division of Movement Disorders, University of Louisville Louisville, Kentucky, United States, 40202 United States, New Jersey University of Medicine and Dentistry, Robert Wood Johnson Medical School New Brunswick, New Jersey, United States, 08901 Germany Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson Beelitz Beelitz-Heilstätten, Germany, 14547 Humboldt Universitat Charite, Campus Virchow, Neurologisch Berlin, Germany, 13353 Universitatsklinikum Carl-Guslav-Carus, Technische Universitat Dresden, Klinik und Poliklinik fur Neurologie Dresden, Germany, 01307 Medizinische Hochschule Hannover, Neurologie 0E 7210 Hannover, Germany, 30625 Zentrum fur Nervenheilkunde. Klinik fur Neurologie mit Poliklinik. Marburg, Germany, 35039 University Hospital Tuebingen,Eberhard-Karls-Universitat, Universitatsklinikum Neurologie Tubingen, Germany, 72076 Spain Hospital de Cruces Barakaldo, Spain, 48902 Fundació Ace Barcelona, Spain, 08014 Dpto.neurologia. H. Clinic. Barcelona, Spain, 08036 Dpt. Neurologia. Hospital Ramón y Cajal. Madrid, Spain, 28034 Hospital U. La Paz Madrid, Spain, 28046 Hospital Puerta del Hierro Madrid, Spain, 28222 Hospital de Donostia San Sebastian, Spain, 20014 Hospital Mutua Terrassa Terrasa, Spain, 8221 Departement of Neurology, Hospital La Fe Valencia, Spain, 460009 United Kingdom The Walton Centre for Neurology and Neurosurgery NHS Trust Liverpool, United Kingdom, L9 7LJ Reta Lila Weston Institute of Neurological Studies,Sara Koe PSP Research Centre London, United Kingdom, WC1N 1PJ Clinical Ageing Research Unit Newcastle upon Tyne, United Kingdom, NE4 5PL Collapse <<
  NCT00948259	Alzheimer´s Disease	Phase 1 Phase 2	Completed	-	Germany ... more >> Pharmacologische Studiecentrum Chemnitz Chemnitz, Germany, 09111 Arzneimittelforschung Leipzig GmbH Leipzig, Germany, 0410Y Studienzentrum PD Dr. Steinwachs Nürnberg, Germany, D- 90402 Collapse <<
  NCT02858908	Myotonic Dystrophy 1	Phase 2	Completed	-	United Kingdom ... more >> Newcastle-upon-Tyne Hospitals NHS Trust Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE1 4LP Collapse <<

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• 参考文献

• [1] Domínguez JM, Fuertes A, et al. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J Biol Chem. 2012 Jan 6;287(2):893-904.

  [2] Martinez A, Castro A, et al. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev. 2002 Jul;22(4):373-84.

  [3] Domoto T, Pyko IV, et al. Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci. 2016 Oct;107(10):1363-1372.

  [4] Zhou A, Lin K, et al. Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol. 2016 Sep;18(9):954-966.

  [5] Wang H, Huang S, et al. Tideglusib, a chemical inhibitor of GSK3β, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim Biophys Acta. 2016 Oct;1860(10):2076-85.

  [6] Khan I, Tantray MA, et al. Natural and synthetic bioactive inhibitors of glycogen synthase kinase. Eur J Med Chem. 2017 Jan 5;125:464-477.

  [7] Luna-Medina R, Cortes-Canteli M, et al. NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders. J Neurosci. 2007;27(21):5766-76.

  [8] Bharathy N, Svalina MN, et al. Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma. Oncotarget. 2017;8(38):62976-62983.

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