(+)-JQ-1isaBETbromodomaininhibitor,withIC50of77nM/33nMforthefirstandsecondbromodomain(BRD4(1/2)).CustomerValidation•NatChemBiol.2016Jul;12(7):504-10.•GenomeRes.2017Nov;27(11):1830-1842.•Leukemia.2017Oct;31(10):2037-2047.•GenesDev.2017Jul19.•PLoSPathog.2016Oct20;12(10):e1005950.•CancerLett.2017May31;402:100-109.•JMedChem.2017Jun22.•Metabolism.2016Oct;65(10):1478-88.•MolCancerTher.2016Jun;15(6):1217-26.•BiochimBiophysActa.2016Dec;1859(12):1527-1537.•ACSChemBiol.2015Aug21;10(8):1770-7.•JBiolChem.2016Nov4;291(45):23756-23768.•JAgricFoodChem.2017Jun7;65(22):4384-4394.•JCellBiochem.2017Jan6.•HarvardMedicalSchoolLINCSLIBRARYDescription(+)-JQ-1isaBETbromodomaininhibitor,withIC50of77nM/33nMforthefirstandsecondbromodomain(BRD4(1/2)).IC50&TargetIC50:77/33nM(BRD4(1/2))[1]InVitro(+)-JQ1representsapotent,highlyspecificandKaccompetitiveinhibitorfortheBETfamilyofbromodomains.(+)-JQ1(100nM,48h)promptssquamousdifferentiationexhibitedbycellspindling,flatteningandincreasedexpressionofkeratin.(+)-JQ1(250nM)inducesrapidexpressionofkeratinintreatedNMC797cellscomparedto(-)-JQ1(250nM)andvehiclecontrols,asdeterminedbyquantitativeimmunohistochemistry.(+)-JQ1(250nM)elicitsatime-dependentinductionofstrong(3+)keratinstainingoftreatedNMC797cells,comparedto(-)-JQ1(250nM)[1].(+)-JQ1isapotentthienodiazepineinhibitor(Kd=90nM)oftheBETfamilycoactivatorproteinBRD4,whichisimplicatedinthepathogenesisofcancerviatranscriptionalcontroloftheMYConcogene.Dose-rangingstudiesof(+)-JQ1demonstratespotentinhibitionofH4Kac4bindingwithaIC50valueof10nMformurineBRDT(1)and11nMforhumanBRDT(1)[2].InVivoPharmacokineticstudiesof(+)-JQ1areperformedinCD1micefollowingintravenousandoraladmiNISTration.Meanplasmaconcentration-timeprofilesof(+)-JQ1afterintravenousdosing(5mg/kg).Thepharmacokineticparametersforintravenous(+)-JQ1demonstrateexcellentdrugexposure(AUC=2090hr*ng/mL)andanapproximatelyonehourhalf-life(T1/2).Meanplasmaconcentration-timeprofilesof(+)-JQ1afteroraldosing(10mg/kg).Thepharmacokineticparametersfororal(+)-JQ1demonstrateexcellentoralbioavailABIlity(F=49%),peakplasmaconcentration(Cmax=1180ng/mL)anddrugexposure(AUC=2090hr*ng/mL)[1].References[1].FilippakopoulosP,etal.SelectiveinhibitionofBETbromodomains.Nature.2010Dec23;468(7327):1067-73.[2].MatzukMM,etal.Small-moleculeinhibitionofBRDTformalecontraception.Cell.2012Aug17;150(4):673-84.[3].PeirsS,etal.TargetingBETproteinsimprovesthetherapeuticefficacyofBCL-2inhibitioninT-cellacutelymphoblasticleukemia.Leukemia.2017Feb3.[4].TögelL,etal.DualTargetingofBromodomainandExtraterminalDomainProteins,andWNTorMAPKSignaling,Inhibitsc-MYCExpressionandProliferationofColorectalCancerCells.MolCancerTher.2016Jun;15(6):1217-26.[5].SahniJM,etal.BromodomainandExtraterminalProteinInhibitionBlocksGrowthofTriple-negativeBreastCancersthroughtheSuppressionofAuroraKinases.JBiolChem.2016Nov4;291(45):23756-23768.[6].NakamuraY,etal.Targetingofsuper-enhancersandmutantBRAFcansuppressgrowthofBRAF-mutantcoloncancercellsviarepressionofMAPKsignalingpathway.CancerLett.2017Aug28;402:100-109.[7].BhattacharyyaS,etal.Alteredhydroxymethylationisseenatregulatoryregionsinpancreaticcancerandregulatesoncogenicpathways.GenomeRes.2017Nov;27(11):1830-1842.PreparingStockSolutionsConcentrationVolumeMass1mg5mg10mg1mM2.1882mL10.9412mL21.8823mL5mM0.4376mL2.1882mL4.3765mL10mM0.2188mL1.0941mL2.1882mLPleaserefertothesolubilityinformationtoselecttheappropriatesolvent.CellAssay[1](+)-JQ1isdissolvedinDMSOandstored,andthendilutedwithappropriatemedia(DMSO0.025%)beforeuse[1].NUTmidlinecarcinomapatientcelllines(797and11060)areplatedinT-25flasksandgrowninDMEM(797)orRPMI(11060)containing10%fetalbovineserumand1%Penicillin/Streptomycin.Cellsaretreatedwitheither250nM(+)-JQ1,250nM(-)-JQ1ortheequivalentvolumeofDMSO(0.025%).Atthedesiredtimepoint,2×106cellsarespunat500×gfor5minutesat4°CandwashedwithPBS.PelletsareresUSPendedin1mLofcoldPBSandaddeddropwisewhilegentlyvortexingto9mL70%ethanolina15mLpolypropylenecentrifugetube.Fixedcellsarethenfrozenat-20°Covernight.Thenextday,cellsarecentrifugedat500×gfor10minutesat4°Candwashedwith3mLofcoldPBS.Cellsareresuspendedin500μLofpropidiumiodidestainingsolution(0.2mg/mLRNAseA,0.02mg/mLpropidiumiodide,0.1%Triton-XinPBS)andincubatedfor20minutesat37°C.SamplesarethentransferredtoiceandanalyzedonaBDFACSCantoII.HistogramsaregeneratedandcellcycleanalysisisperformedusingFlowJoflowcytometryanalysissoftware[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalAdministration[1][2](+)-JQ1isformulatedforintravenousinjectionin10%DMSOand10%HP-β-CD(Mice)[1].(+)-JQ1isformulatedinsaline,10%2-Hydroxypropyl-β-cyclodextrinand10%DMSO(Rat)[2].Mice[1]MaleCD1mice(24-29g)aretreatedwithasingledoseof(+)-JQ1at5mg/kgforintravenoustailveininjectionstudiesand10mg/kgfororalgavagestudies.Approximately150μLofbloodaretakenfromanimalsbyretro-orbitalpunctureunderanesthesiawithIsofluraneintoEDTAtubesatpre-specifiedtimeintervals:0.033,0.083,0.25,0.5,1,2,4,5,8and24hours.Threeanimalsareanalyzedpertimepoint.Bloodsamplesareputoniceandcentrifugedtoobtainplasmasamples(2000×g,5minunder4°C)within15minutespost-sampling.Plasmasamplesarestoredatapproximately-70°Cuntilanalysisisperformed.Miceareprovidedfreeaccesstofoodandwaterthroughoutthestudy.Rat[2]AdultmaleSprague-Dawleyratsaretreatedwithvehicleor(+)-JQ1(10mg/kg).TreatmentisadministeredIPat1/100bodymass.Ratsarecheckedtwice-dailyformortalityandweighedondays1,3,7,14,and21.Thetreatmentregimenutilized4daysof50mg/kgJQ1administereddailywhichisdecreasedto10mg/kgtwicedailyfortheremainderofthestudyduetotheappearanceofadverseeffectsinasubsetofanimals.Forallanimalscompleting3weeksoftreatment,testismass,spermmotility,andspermcountsaredeterminedasdescribedformousestudies.Inbrief,testesarefixedinBouin’sandpreparedforhistology.TheotherhalfismincedinwarmM16bufferandusedforspermcountsandmotilitystudies.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.References[1].FilippakopoulosP,etal.SelectiveinhibitionofBETbromodomains.Nature.2010Dec23;468(7327):1067-73.[2].MatzukMM,etal.Small-moleculeinhibitionofBRDTformalecontraception.Cell.2012Aug17;150(4):673-84.[3].PeirsS,etal.TargetingBETproteinsimprovesthetherapeuticefficacyofBCL-2inhibitioninT-cellacutelymphoblasticleukemia.Leukemia.2017Feb3.[4].TögelL,etal.DualTargetingofBromodomainandExtraterminalDomainProteins,andWNTorMAPKSignaling,Inhibitsc-MYCExpressionandProliferationofColorectalCancerCells.MolCancerTher.2016Jun;15(6):1217-26.[5].SahniJM,etal.BromodomainandExtraterminalProteinInhibitionBlocksGrowthofTriple-negativeBreastCancersthroughtheSuppressionofAuroraKinases.JBiolChem.2016Nov4;291(45):23756-23768.[6].NakamuraY,etal.Targetingofsuper-enhancersandmutantBRAFcansuppressgrowthofBRAF-mutantcoloncancercellsviarepressionofMAPKsignalingpathway.CancerLett.2017Aug28;402:100-109.[7].BhattacharyyaS,etal.Alteredhydroxymethylationisseenatregulatoryregionsinpancreaticcancerandregulatesoncogenicpathways.GenomeRes.2017Nov;27(11):1830-1842.MolecularWeight456.99FormulaC₂₃H₂₅ClN₄O₂SCASNo.1268524-70-4StoragePowder-20°C3years 4°C2yearsInsolvent-80°C6months -20°C1monthShippingRoomtemperatureincontinentalUS;mayvaryelsewhereSolvent&SolubilityDMSO:≥45mg/mL(+)-JQ-1(JQ1)isformulatedin10%DMSOand90%ofa10%2-hydroxypropyl-β-cyclodextrinsolution[3].(+)-JQ-1(JQ1)ispreparedinvehicle(20%hydroxypropyl-β-cyclodextrin,5%DMSO,0.2%Tween-80insaline)[4].(+)-JQ-1(JQ1)ispreparedinvehicle(1:1propyleneglycol:water)[5].(+)-JQ-1(JQ1)ispreparedinvehicle(5%DMSOin10%2-hydroxypropyl-ß-cyclodextrinsolution)[6].(+)-JQ-1ispreparedinvehicle(10%hydroxypropylβ-cyclodextrininwater)[7].*"

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