生物活性

• 靶点	GSK-3β IC50:53nM

• 描述GSK-3β is a serine/threonine kinase that plays a role in a broad range of activities in the cell. GSK-3β is an essential regulator in the WNT/ β-catenin pathway where it phosphorylates β-catenin committing it to degradation^[3]. IM-12, a GSK-3β inhibitor, showed a bell-shaped dose-response relationship in a kinase activity assay of inhibition of GSK-3β, and itscalculated IC₅₀ was 53 nM (luminescent kinase activity assay) ^[4]. Treatment of 3μM IM-12 had an ability to attenuate ReNcell VM cell's proliferation (human neural progenitor cell line) in 72 h, increase nuclear accumulation of β-catenin in ST14A cells in 6h, upregulate TCF activity in ReNcell VM cells ( transfected with TOP/FOP plasmids or co-transfected with pCAGGS-S33Y) in 24h, and promote neuronal differentiation from ReNcell VM cells to f βIIItub+ cells in 3d , ^[4]. In a pig model of metabolic syndrome and chronic myocardial ischemia, treatment of IM-12(1.5mg/kg, daily) for 5 weeks improved vessel density in the ischemic and non-ischemic myocardial tissue, and increased myocardial blood flow both at rest and with pacing ^[5].
• 作用机制IM-12 inhibits GSK-3β to activate Wnt-β catenin signaling pathway, which induces the decay of the degradation complex, stabilizing β catenin which then translocates into the nucleus where it binds to the T-cell factor (TCF)/lymphoid enhancer factor (LEF)-complex and regulates the transcription of Wnt-specific target genes ^[4].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  ReNcell VM cells	3 uM	Proliferation assay	72 h	Antiproliferative activity against human ReNcell VM cells assessed as reduction of cell proliferation at 3 uM after 72 hrs	20708937
  ST14A cells	-	Function assay	6 h	Inhibition of GSK-3-beta-mediated Wnt signaling in human ST14A cells assessed as increase in accumulation of beta-casein around nucleus after 6 hrs by microscopic analysis	20708937

• 动物研究
  剂量	Rat: 25 mg/kg[2] (i.p.)
  给药途径	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
  NCT02891395	Graft Versus Host Disease	Phase 2	Active, not recruiting	December 2018	Belgium ... more >> CHU Sart Tilman Liège, Belgium France CHU d'Amiens Amiens, France CHU d'Angers Angers, France CHU Besançon Besancon, France CHU Bordeaux Bordeaux, France Hopital Morvan Brest, France CHU Clémenceau Caen, France HIA de Percy Clamart, France CHU de Clermont Ferrand Clermont Ferrand, France CHU Grenoble Grenoble, France Diseases of Blood Service HURIEZ hospital CHRU de LILLE LIlle, France, 59037 Centre hospitalier et régional de Lille Lille, France CHU de Lyon Lyon, France Institut Paoli Calmettes Marseille, France Hôpital Saint Eloi Montpellier, France CHU Hotel Dieu Nantes, France CHU de Nice Nice, France Hopital NECKER Paris, France Hôpital pitié Salpetrière Paris, France Centre Henri Becquerel Rouen, France CHU de STRASBOURG Strasbourg, France CHU Purpan Toulouse, France Collapse <<

• 参考文献

• [1] Schmole AC, Brennfuhrer A, et al. Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. Bioorg Med Chem. 2010 Sep 15;18(18):6785-95.

  [2] Wang T, Duan YM, et al. IM-12 activates the Wnt-β-catenin signaling pathway and attenuates rtPA-induced hemorrhagic transformation in rats after acute ischemic stroke. Biochem Cell Biol. 2019 Dec;97(6):702-708.

  [3] Ke B, Lu R, Zhang X. Phosphorylated Glycogen Synthase Kinase-3β (GSK-3β) Improves Cognition in Rats with Diabetes-Associated Cognitive Decline. Med Sci Monit. 2019 May 6;25:3336-3343. doi: 10.12659/MSM.914653. Retraction in: Med Sci Monit. 2019 Aug 21;25:6291. PMID: 31057171

  [4] Schmöle AC. Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. Bioorg Med Chem. 2010 Sep 15;18(18):6785-95. doi: 10.1016/j.bmc.2010.07.045. Epub 2010 Jul 25.

  [5] Potz BA. Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis. J Thorac Cardiovasc Surg. 2017 Feb;153(2):342-357. doi: 10.1016/j.jtcvs.2016.09.087. Epub 2016 Nov 16.

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