Trametinib-DMSO-solvate-GSK-1120212-DMSO-solvate-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemETrametinib(DMSOsolvate)Cat.No.:HY-10999ACASNo.:1187431-43-1Synonyms:GSK-1120212(DMSOsolvate);JTP-74057(DMSOsolvate)分⼦式:C₂₈H₂₉FIN₅O₅S分⼦量:693.53作⽤靶点:MEK;Apoptosis作⽤通路:MAPK/ERKPathway;Apoptosis储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:69mg/mL(99.49mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.4419mL7.2095mL14.4190mL5mM0.2884mL1.4419mL2.8838mL10mM0.1442mL0.7209mL1.4419mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.5mg/mL(3.60mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(3.60mM);Suspendedsolution;Needultrasonic3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(3.60mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Trametinib(DMSOsolvate)(GSK-1120212(DMSOsolvate);JTP-74057(DMSOsolvate))⼝服有效的MEK抑制剂，抑制MEK1和MEK2的IC50分别为2nM。Trametinib(DMSOsolvate)可以激活⾃噬(autophagy)，诱导凋亡(apoptosis)。IC50&TargetMEK1MEK22nM(IC50)2nM(IC50)体外研究InBRAFmutantSK-MEL-28cellsandKRASmutantHCT116cells,Trametinib(GSK1120212;JTP-74057)DMSOsolvatecausesdose-dependentinhibitionofERK1/2phosphorylationaswellasdose-dependentgrowthinhibition.InbothSK-MEL-28andHCT116cells,TrametinibDMSOsolvateinhibits50%p-ERK1/2atnearlyequivalentconcentrations(0.8and1.8nM,respectively).However,astheslopesofthecurvesreflect,inSK-MEL-28cells,TrametinibDMSOsolvateinhibits90%p-ERK1/2atalowerconcentration(3.4nM)thaninHCT116(33.3nM).Furthermore,inbothcelllines,50%growthinhibitionisonlyachievedatconcentrationsTrametinibDMSOsolvatethatproducesnearcompleteERK1/2inhibition(85and90%,respectively)[2].体内研究Trametinib(GSK1120212;JTP-74057)DMSOsolvateisevaluatedinvivoinanA549(KRASmutantcellline)xenograftmodel,orallydosingdailyfor21days(qd×21).Inthisstudy,nearcompletetumorgrowthinhibitionisobservedat5.0and2.5mg/kg[92and87%tumorgrowthinhibition(TGI),respectively]andtoalesserdegreeat0.5and0.1mg/kg(62and58%TGI).Although5mg/kgisthemaximallytolerateddose(MTD)inthisstudy,3mg/kgisthetypicallyobservedMTD.Dose-dependentantitumoractivitywithTrametinibDMSOsolvatetreatmenthasbeensimilarlyreportedforseveralotherKRASandBRAFmutanttumormodels[2].PROTOCOLCellAssay[2]SK-MEL-28,andHCT116celllinesareplatedintriplicate96wellmicrotitreplatesat5000cellsperwellinculturemedia.TrametinibdissolvedinDMSOornegativecontrol(0.1%DMSO)areaddedthefollowingdayandoneplateisharvestedwith50μLofCellTiter-Gloforatime0(T=0)measurement.Remainingduplicatecellplatesaretypicallyincubatedfor72h.Cellsarethenlysedwith50μLCellTiter-Glo,andchemiluminescentsignalisreadontheWallacEnVision2100platereader.FormeasurementofcellularERK1/2phosphorylation,cellsareseededandtreatedwithTrametinib,andlysedafter72hinTrislysisbuffersupplementedwithphosphataseandproteaseinhibitors.Allsamplesareanalyzedwithaphospho-ERK1/2ELISA.PlatesarereadonMSD.SI6000andcurvesareanalyzedusingtheXLfitcurve-fittingtool.ForcomparisonofthegrowthassaycurveandpERK1/2assaycurve,dataarebackgroundsubtractedand2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEnormalizedtothevehicletreatmentcontrol[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[2]Administration[2]A549(humannon-smallcelllungcarcinoma)modelisestablishedfromcellsgrownintissuecultureandharvestedasepticallyusingatrypsindigest.Femaleathymicmice(strainnu/nu)areinjectedsubcutaneouslywithbetween5×106and107cellsin50%martigel.Tumorsareallowedtoestablishforonetofourweeksbeforeuse.Trametinibisadministeredorallyattheindicateddosesin0.2mL/20gbyweight.TumorsaremeasuredtwiceweeklyusingVerniercalipers.Antitumoractivityisdefinedastumorgrowthinhibitionrepresentingthe%volumedifferentialintumorgrowthbetweenthetreatedandcontroltumorsatthetimevehicletumorsexceededavolumeof1000mm3.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•Cell.2018Aug9;174(4):843-855.e19.•CancerCell.2021Aug9;39(8):1135-1149.e8.•CancerCell.2021May10;39(5):678-693.e11.•CancerCell.2020Mar16;37(3):387-402.e7.•CancerDiscov.2020Jun;10(6):872-887.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].YamaguchiT,etal.SuppressiveeffectofanorallyactiveMEK1/2inhibitorintwodifferentanimalmodelsforrheumatoidarthritis:acomparisonwithHWA486.InflammRes,2012,61(5),445-454.[2].AbeH,etal.DiscoveryofaHighlyPotentandSelectiveMEKInhibitor:GSK1120212(JTP