SB216763ispotentandselectiveglycogensynthasekinase-3(GSK-3)inhibitor,withIC₅₀valueof34.3nMforGSK-3αandGSK-3β,respectively.

IC50:34.3nM(GSK-3α),34.3nM(GSK-3β)^[5]

SB-216763(10-20µM)inducesβ-cateninmediated-transcriptioninadose-dependentmannerinHEK293cells.SB-216763(10,15and20µM)canmaintainmESCswithapluripotent-likemorphologyinlong-termculture.SB-216763(10µM)canmaintainJ1mESCsinapluripotentstateformorethanamonth^[2].SB-216763inhibitsGSK-3withIC₅₀of34nM^[3].SB-216763isequallyeffectiveatinhibitinghumanGSK-3αandGSK-3β^[5].

SB216763(20mg/kg,i.v.)significantlyimprovesthesurvivalofBLM-treatedmice.MicerandomizedtoreceiveBLMplusSB216763showsanoteworthyreduction,comparedwithBLM-treatedmice.SB216763(20mg/kg,i.v.)reducesthemagnitudeofBLM-inducedalveolitis^[1].SB216763(0.2mg/kg,i.v.)witheither17β-E₁₀₀orGeni₁₀₀reversestheceilingeffectbecausetheseagentssignificantlyreduceinfarctsizewhentherabbits"heartsaresubmittedto30-minCAO^[4].

• [1].Gurrieri,etal.3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(SB216763),aglycogensynthasekinase-3inhibitor,displaystherapeuticpropertiesinamousemodelofpulmonaryinflammationandfibrosis.J.Pharmacol.Exp.Ther.2010

  [2].KirbyLA,etal.Glycogensynthasekinase3(GSK3)inhibitor,SB-216763,promotespluripotencyinmouseembryonicstemcells.PLoSOne.2012;7(6):e39329.Epub2012Jun26.

  [3].WangM,etal.Thefirstsynthesisof[(11)C]SB-216763,anewpotentialPETagentforimagingofglycogensynthasekinase-3(GSK-3).BioorgMedChemLett.2011Jan1;21(1):245-9.Epub2010Nov11.

  [4].TheceilingeffectofpharmacologicalpostconditioningwiththephytoestrogengeNISTeinisreversedbytheGSK3betainhibitorSB216763[3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione]throughmitochondrialATP-dependentpotassiumchannelopening.

  [5].CoghlanMP,etal.Selectivesmallmoleculeinhibitorsofglycogensynthasekinase-3modulateglycogenmetabolismandgenetranscription.ChemBiol.2000Oct;7(10):793-803.

  [6].WangW,etal.Inhibitionofglycogensynthasekinase3betaamelioratestriptolide-inducedacutecardiacinjurybydesensitizingmitochondrialpermeABIlitytransition.ToxicolApplPharmacol.2016Dec15;313:195-203.

SB-216763isdissolvedin0.1%DMSO.

MESCsmaintainedwithLIFor10µMSB-216763formorethanamonthareresUSPendedat40,000cells/mLinLIF-freemESCmedium.EBsarepreparedbyahangingdropprocedure.Briefly,20µLdropscontainingmESCsarePipettedontheinsideofa10-cmPetridishlid.ThelidsareplacedontoPetridishescontaining10mLofHBSSandtheEBsareallowedtoformandgrowfor4daysintheincubator.After4days,15-20EBsaretransferredtoawellcontainingLIF-freemESCmediumina24-wellplate.Themediumisexchangedeverytwodaysandautonomouslybeatingcellaggregatesareobservedandcounted.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

SB216763isdissolvedinvehicle(25%dimethylsulfoxide,25%polyethyleneglycol,and50%saline).

Miceareallocatedtofourgroups(n=12/group)asfollows:1)intratrachealsaline+vehicle(25%dimethylsulfoxide,25%polyethyleneglycol,and50%saline),2)intratrachealsaline+SB216763(20mg/kg)dissolvedinvehicle,3)intratrachealBLM(3U/kg)+vehicle,and4)intratrachealBLM+SB216763(20mg/kg)invehicle.Anothersetofexperimentstoassesscytokineexpressionbyreversetranscription-PCRisconductedinthemice(n=12/group)toreceive1)intratrachealsaline+vehicle,2)intratrachealBLM,and3)intratrachealBLM+SB216763.Toinducepulmonaryfibrosis,BLMisintratracheallyadministeredinmice(n=15/group)onday0.BLMandsaline-treatedmiceareadministeredwithSB216763dissolvedinvehicleorvehiclealoneintravenouslyatday0andthenintraperitoneallytwiceaweekuntilday28.MicearesacrificedbyCO₂ inhalationondays2,7,and28.IntheterminaldeoxynucleotidyltransferasedUTPnick-endlabeling(TUNEL)experiments,thecohortsofmiceareasfollows:saline-treated(n=6),BLM-treated(n=6),andBLM+SB216763-treated(n=6).MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].Gurrieri,etal.3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(SB216763),aglycogensynthasekinase-3inhibitor,displaystherapeuticpropertiesinamousemodelofpulmonaryinflammationandfibrosis.J.Pharmacol.Exp.Ther.2010

  [2].KirbyLA,etal.Glycogensynthasekinase3(GSK3)inhibitor,SB-216763,promotespluripotencyinmouseembryonicstemcells.PLoSOne.2012;7(6):e39329.Epub2012Jun26.

  [3].WangM,etal.Thefirstsynthesisof[(11)C]SB-216763,anewpotentialPETagentforimagingofglycogensynthasekinase-3(GSK-3).BioorgMedChemLett.2011Jan1;21(1):245-9.Epub2010Nov11.

  [4].TheceilingeffectofpharmacologicalpostconditioningwiththephytoestrogengenisteinisreversedbytheGSK3betainhibitorSB216763[3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione]throughmitochondrialATP-dependentpotassiumchannelopening.

  [5].CoghlanMP,etal.Selectivesmallmoleculeinhibitorsofglycogensynthasekinase-3modulateglycogenmetabolismandgenetranscription.ChemBiol.2000Oct;7(10):793-803.

  [6].WangW,etal.Inhibitionofglycogensynthasekinase3betaamelioratestriptolide-inducedacutecardiacinjurybydesensitizingmitochondrialpermeabilitytransition.ToxicolApplPharmacol.2016Dec15;313:195-203.

371.22

C₁₉H₁₂Cl₂N₂O₂

280744-09-4

RoomtemperatureincontinentalUS;mayvaryelsewhere

10mMinDMSO

SB216763isdissolvedinDMSOtomakestocksolutionsandthensuspendedinnormalsaline^[6].

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1].Gurrieri,etal.3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(SB216763),aglycogensynthasekinase-3inhibitor,displaystherapeuticpropertiesinamousemodelofpulmonaryinflammationandfibrosis.J.Pharmacol.Exp.Ther.2010

  [2].KirbyLA,etal.Glycogensynthasekinase3(GSK3)inhibitor,SB-216763,promotespluripotencyinmouseembryonicstemcells.PLoSOne.2012;7(6):e39329.Epub2012Jun26.

  [3].WangM,etal.Thefirstsynthesisof[(11)C]SB-216763,anewpotentialPETagentforimagingofglycogensynthasekinase-3(GSK-3).BioorgMedChemLett.2011Jan1;21(1):245-9.Epub2010Nov11.

  [4].TheceilingeffectofpharmacologicalpostconditioningwiththephytoestrogengenisteinisreversedbytheGSK3betainhibitorSB216763[3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione]throughmitochondrialATP-dependentpotassiumchannelopening.

  [5].CoghlanMP,etal.Selectivesmallmoleculeinhibitorsofglycogensynthasekinase-3modulateglycogenmetabolismandgenetranscription.ChemBiol.2000Oct;7(10):793-803.

  [6].WangW,etal.Inhibitionofglycogensynthasekinase3betaamelioratestriptolide-inducedacutecardiacinjurybydesensitizingmitochondrialpermeabilitytransition.ToxicolApplPharmacol.2016Dec15;313:195-203.