MLN4924isapotentandselectiveNEDD8-activatingenzyme(NAE)inhibitorwithIC50of4.7nM.CustomerValidation•NatCommun.2017May22;8:15398.•Elife.2016Apr11;5.pii:e14087.•Oncotarget.2017Sep23;8(49):86395-86409.•Oncotarget.2016Oct4;7(40):66087-66099.•Oncotarget.2016Jun14;7(24):35643-35654.•AmJPhysiolLungCellMolPhysiol.2017Jul1;313(1):L104-L114.•Virology.2015Mar;477:10-7.•AnnHematol.2014Sep;93(9):1499-508.•BiochemBiophysResCommun.2017Jan29;483(1):223-229.•TechnolCancerResTreat.2016Aug;15(4):527-34.•UlmUniversity.13-01-2017.DescriptionMLN4924isapotentandselectiveNEDD8-activatingenzyme(NAE)inhibitorwithIC50of4.7nM.IC50&TargetIC50:4.7nM(NAE)[1]InVitroMLN4924isapotentinhibitorofNAE,andisselectiverelativetothecloselyrelatedenzymesUAE,SAE,UBA6andATG7(IC50=1.5,8.2,1.8and>10μM,respectively)whenevaluatedinpurifiedenzymeassaysthatmonitortheformationofE2-UBLthioesterreactionproducts.MLN4924selectivelyinhibitsNAEactivitycomparedtothecloselyrelatedubiquitin-activatingenzyme(UAE,alsoknownasUBA1)andSUMO-activatingenzyme(SAE;aheterodimerofSAE1andUBA2subunits),inpurifiedenzymeandcellularassays.MLN4924exhibitspotentcytotoxicactivityagainstavarietyofhumantumour-derivedcelllines[1].InVivoMLN4924(sc,10mg/kg,30mg/kg,or60mg/kg)inhibitstheNEDD8pathwayresultinginDNAdamageinMicebearingHCT-116xenografts[1].Pevonedistat(sc,120mg/kg)andTNF-α(10μg/kg)synergisticallycauseliverdamageinSDrats[2].ClinicalTrialViewMoreCollapseReferences[1].SoucyTA,etal.AninhibitorofNEDD8-activatingenzymeasanewapproachtotreatcancer.Nature.2009Apr9;458(7239):732-6.[2].FSWolenski,etal.TheNAEinhibitorpevonedistat(MLN4924)synergizeswithTNF-αtoactivateapoptosis.CellDeathDiscovery1,Articlenumber:15034(2015)PreparingStockSolutionsConcentrationVolumeMass1mg5mg10mg1mM2.2547mL11.2734mL22.5469mL5mM0.4509mL2.2547mL4.5094mL10mM0.2255mL1.1273mL2.2547mLPleaserefertothesolubilityinformationtoselecttheappropriatesolvent.CellAssay[1]MLN4924isdissolvedinDMSOandstored,andthendilutedwithappropriatemediumbeforeuse[1].HCT-116cellsgrownin6-wellcell-culturedishesaretreatedwith0.1%DMSO(control)or0.3μMMLN4924for24h.Wholecellextractsarepreparedandanalysedbyimmunoblotting.ForanalysisoftheE2-UBLthioesterlevels,lysatesarefractionatedbynon-reducingSDS-PAGEandimmunoblottedwithpolyclonalantibodiestoUbc12,Ubc9andUbc10.Foranalysisofotherproteins,lysatesarefractionatedbyreducingSDS-PAGEandprobedwithprimaryantibodiesasfollows:mousemonoclonalantibodiestoCDT1,p27,geminin,ubiquitin,securin/PTTGandp53orrabbitpolyclonalantibodiestoNRF2,CyclinB1andGADD34[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalAdmiNISTration[1][2]MLN4924isdissolvedinDMSOandthendilutedwithPBSorsaline.Mice[1]MicebearingHCT-116tumoursof300-500mm3areadministeredasingleMLN4924dose(of10,30or60mg/kg),andtumorsareexcisedatvarioustime-pointsoverthesubsequent24hperiod.TherelativelevelsofNEDD8-cullinandNRF2areestimatedbyquantitativeimmunoblotanalysisusingAlexa680-labelledanti-IgGasthesecondaryantibody.ThestatisticaldifferencebetweenthegroupsforNEDD8-cullininhibitionisdeterminedusingtheKruskal-Wallistest.FortheanalysisofCDT1andphosphorylatedCHK1(Ser317)levelsintumoursections,formalin-fixed,paraffin-embeddedtumoursectionsarestainedwiththerelevantantibodies,amplifiedwithHRP-labelledsecondaryantibodiesanddetectedwiththeChromoMapDABKit.Slidesarecounterstainedwithhaematoxylin.ImagesarecapturedusinganEclipseE800microscopeandRetigaEXicolourdigitalcameraandprocessedusingMetamorphsoftware.CDT1andphosphorylatedCHK1levelsareexpressedasafunctionoftheDABsignalarea.Rat[2]Ten-week-oldmaleSprague-Dawleyratsareused.Acrosstwostudies,atotalofeightanimalsineachgrouparedosedwithvehicle,TNF-α,MLN4924,orMLN4924+TNF-α.Animalsarefirstintravenouslyadministeredeithervehicle(1×PBS)or10μg/kgTNF-α.Onehourlater,theyaresubcutaneouslyadministeredvehicle(20%sulfobutyletherbeta-cyclodextrinin50mMcitratebuffer,pH3.3)or120mg/kgMLN4924.Scheduledeuthanasiaoccurred24hpostdose.Unscheduledeuthanasiaisperformedwhenanimalsexhibitedmoribundconditions.SerumiscollectedatnecropsyandanalyzedbyIdexxLaboratoriesforserumchemistryMarkersofliverdamage.Additionally,theliversfromfiveanimalsineachgroupareremoved,separatedintotwosectionsandeitherfrozenat-80°Cforsubsequentproteinanalysisorfixedin10%neutralbufferedformalin,embeddedinparaffin,sectionedat4-6μm,mountedonglassslides,stainedwithhematoxylinandeosin,andanalyzedwithanOlympusBX51lightmicroscopeforhistopathologyassessment.Microscopicfindingsarerecordedinconcordancewiththestandardizednomenclatureforclassifyinglesionswithintheliversofrats.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.References[1].SoucyTA,etal.AninhibitorofNEDD8-activatingenzymeasanewapproachtotreatcancer.Nature.2009Apr9;458(7239):732-6.[2].FSWolenski,etal.TheNAEinhibitorpevonedistat(MLN4924)synergizeswithTNF-αtoactivateapoptosis.CellDeathDiscovery1,Articlenumber:15034(2015)MolecularWeight443.52FormulaC₂₁H₂₅N₅O₄SCASNo.905579-51-3StoragePowder-20°C3years 4°C2yearsInsolvent-80°C6months -20°C1monthShippingRoomtemperatureincontinentalUS;mayvaryelsewhereSolvent&SolubilityDMSO:≥111.25mg/mL*"

托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-Tropanylindole-3-carboxylate;lαH，5Αh-Tropan-3α-ylindole-3-carboxylate中文名称:托烷司琼中文同义词:托普西隆;托普西龙;曲匹西龙;托烷司琼;Β-托烷司琼;CS-348;Β-内托烷司琼;吲哚-3-甲酰氯;Β-托烷司琼(光学异构体);Β-托烷司琼,托烷司琼异构体CBNumber:CB3236404分子式:C17H20N2O2分子量:284.35MOLFile:89565-68-4.mol化学性质安全信息用途供应商112化学性质安全信息用途供应商112托烷司琼化学性质熔点:201-202°C沸点:448.5±35.0°C(Predicted)密度:1.26储存条件:2-8°C溶解度:H2O:soluble形态:solid酸度系数(pKa):15.38±0.30(Predicted)颜色:whiteCAS数据库:Chemicalbook89565-68-4(CASDataBaseReference)安全信息WGKGermany:3托烷司琼化学药品说明书托烷司琼|药物应用信息托烷司琼性质、用途与生产工艺临床评价Sorbe等报道本品对含顺铂(剂量50～89mg/m2)化疗方案引起的急性呕吐完全控制率为63%。58例恶性肿瘤化疗所致恶心、呕吐者，应用托烷司琼或昂丹司琼8mg分别在同一病人前后2个化疗周期的第1d给药前30min静脉注射，并用地塞米松10mg静脉滴注。结果两药控制急性及迟发性恶心、呕吐的疗效基本相似，均可达81%～100%。本品对强致吐化疗药物顺铂的止吐疗效突出。药物相关作用饮食可略为延长本品的吸收。本品与利福平、苯巴比妥等肝酶诱导药同时使用，可加快代谢，故快代谢型者需增加剂量，慢者则不必。西咪替丁等肝酶抑制药对本品血药浓度无明显影响。适应症托烷司琼临床用于预防和治疗癌症化疗引起的恶心和呕吐。化学性质结晶，熔点201-202℃(二氯甲烷-乙酸乙酯)。单盐酸托烷司琼(TropisetronMonohydroehloride)：C17H20N2O2?HCI。[105826-92-4]。熔点283-285℃(分解)。用途有高效性和选择性的5-HT3受体拮抗剂。用于化疗所致的呕吐。用途为5-羟色胺拮抗药生产方法托品醇(I)和酰氯(Ⅱ)反应，可得托烷司琼。托烷司琼上下游产品信息上游原料托品醇下游产品