Trametinib-DMSO-solvate-GSK-1120212-DMSO-solvate-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemETrametinib(DMSOsolvate)Cat.No.:HY-10999ACASNo.:1187431-43-1Synonyms:GSK-1120212(DMSOsolvate);JTP-74057(DMSOsolvate)分?式:C??H??FIN?O?S分?量:693.53作?靶點(diǎn):MEK;Apoptosis作?通路:MAPK/ERKPathway;Apoptosis儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:69mg/mL(99.49mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM1.4419mL7.2095mL14.4190mL5mM0.2884mL1.4419mL2.8838mL10mM0.1442mL0.7209mL1.4419mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.5mg/mL(3.60mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(3.60mM);Suspendedsolution;Needultrasonic3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(3.60mM);ClearsolutionBIOLOGICALACTIVITY?物活性Trametinib(DMSOsolvate)(GSK-1120212(DMSOsolvate);JTP-74057(DMSOsolvate))?服有效的MEK抑制劑，抑制MEK1和MEK2的IC50分別為2nM。Trametinib(DMSOsolvate)可以激活?噬(autophagy)，誘導(dǎo)凋亡(apoptosis)。IC50&TargetMEK1MEK22nM(IC50)2nM(IC50)體外研究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].體內(nèi)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?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?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