MKC3946-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEMKC3946Cat.No.:HY-19710CASNo.:1093119-54-0分⼦式:C₂₁H₂₀N₂O₃S分⼦量:380.46作⽤靶点:IRE1作⽤通路:CellCycle/DNADamage储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:20mg/mL(52.57mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.6284mL13.1420mL26.2840mL5mM0.5257mL2.6284mL5.2568mL10mM0.2628mL1.3142mL2.6284mL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>>90%(20%SBE-β-CDinsaline)Solubility:≥2mg/mL(5.26mM);Clearsolution1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEBIOLOGICALACTIVITY⽣物活性MKC3946⼀种有效的IRE1α抑制剂，常⽤于癌症研究。体外研究MKC-3946blocksXBP1mRNAsplicingandexhibitscytotoxicityagainstAMLcells.MKC-3946inhibitsXBP1Sexpressioninducedbytunicamycin(TM)inNB4cells(B)andAMLsamplefrompatients[1].MKC-3946preventsthesplicingoftheXBP1mRNAinresponsetoERstresscausedbymutantproinsulinproduction[2].MKC-3946isanIRE1αendoribonucleasedomaininhibitorthatblocksXBP1mRNAsplicingandtriggersmodestgrowthinhibitioninMMcells.MKC-3946inhibitsXBP1sexpressioninducedbyTminadose-dependentmanner,butdoesnotaffectphosphorylationofIRE1α.MKC-3946blocksXBP1splicingandenhancescytotoxicityinducedbybortezomibor17-AAG.MKC-3946(10μM)enhancesERstress-mediatedapoptosisinducedbybortezomibor17-AAG,andenhancescytotoxicityofERstressors,eveninthepresenceofBMSCsorexogenousIL-6[3].体内研究MKC-3946(100mg/kg,i.p.)inhibitsXBP1splicinginamodelofERstressinvivo,associatedwithsignificantgrowthinhibitionofMMcells,aloneorwithbortezomib.MKC-3946significantlyreducesMMtumorgrowthinthetreatmentversuscontrolgroup.InhibitionofXBP1splicingbyMKC-3946isassociatedwithdecreasedMMgrowthinvivo,aloneorincombinationwithbortezomib[3].PROTOCOLCellAssay[1]CellproliferationandviabilityareexaminedusingMTTassay.Foreachassay,variousnumberofcells(1,000forcellproliferationand10,000forcellviabilityassays)areseededin96-wellplates,followedbyeithervehicle(DMSO)orincreasingconcentrationsofdrug.Fordetectionofrelativenumbersoflivingcells,10μLofMTT(5mg/mL)isaddedtoeachwell,placedinanincubatorforfourhours,followedbycentrifugation(1,000rpm,5min);100μLofsupernatantmediafromeachwellarecarefullyremovedand100μLofSDSbuffer(20%inwater)isaddedtodissolvethecrystals.Resultsarefurtherreadonspectrophotometermachineat570nMwavelength.Halfmaximalinhibitoryconcentration(IC50)iscalculatedusingtheGraphPadPrism5.SynergyofcombinationoftwodrugsisdeterminedusingtheCalcuSynsoftware.Theextentofdruginteractionbetweenthetwodrugsisdeterminedusingthecombinationindex(CI)formutuallyexclusivedrugs.DifferentCIvaluesareobtainedwhensolvingtheequationfordifferentconcentrationsofdrugs.ACIof1indicatesanadditiveeffect,whereasaCIof<1denotessynergy.Allexperimentsarerepeatedatleastthreetimes.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalCB17SCIDmice(48-54daysold)areareinjectedsubcutaneouslywith1×107RPMI8226cellsmixedwithAdministration[3]Matrigelonday0,andreceivetreatmentfor21daysstartingonday1.Miceareassignedinto4groups(n=8):dailyintraperitonealinjectionsof100mg/kgMKC-3946;intravenousinjectionsof0.15mg/kgbortezomibtwiceaweek;acombinationofMKC-3946intraperitoneallywithbortezomibintravenously;and10%HPBCDintraperitoneallywithnormalsalineintravenouslyasavehiclecontrol.Tumorvolumeiscalculatedfromcalipermeasurementsevery3to4days;micearekilledwhentumorsreach1.5cminlength.Survivalisevaluatedfromthefirstdayoftreatmentuntildeath.2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEMCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•EMBOMolMed.2021Nov29;e14678.•CellDeathDiscov.2022Oct4;8(1):407.•JAgricFoodChem.2022Feb2;70(4):1293-1303.•JCellMolMed.2020Aug;24(16):9428-9438.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].SunH,etal.InhibitionofIRE1α-drivenpro-survivalpathwaysisapromisingtherapeuticapplicationinacutemyeloidleukemia.Oncotarget.2016Apr5;7(14):18736-49[2].ZhangL,etal.IRE1inhibitionperturbstheunfoldedproteinresponseinapancreaticβ-celllineexpressingmutantproinsulin,butdoesnotsensitizethecellstoapoptosis.BMCCellBiol.2014Jul10;15:29.[3].MimuraN,etal.BlockadeofXBP1splicingbyinhibitionofIRE1αisapromisingtherapeuticoptioninmu