Ceritinib-LDK378-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemECeritinibCat.No.:HY-15656CASNo.:1032900-25-6Synonyms:LDK378分⼦式:C₂₈H₃₆ClN₅O₃S分⼦量:558.14作⽤靶点:Anaplasticlymphomakinase(ALK);InsulinReceptor;IGF-1R作⽤通路:ProteinTyrosineKinase/RTK储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:5.6mg/mL(10.03mM;Needultrasonic)Ethanol:≥3.33mg/mL(5.97mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM1.7917mL8.9583mL17.9167mL5mM0.3583mL1.7917mL3.5833mL10mM0.1792mL0.8958mL1.7917mL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1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE、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%salineSolubility:≥0.5mg/mL(0.90mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥0.5mg/mL(0.90mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥0.5mg/mL(0.90mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Ceritinib(LDK378)⼀种选择性，具有⼝服活性的且具有ATP竞争性的ALK酪氨酸激酶抑制剂，IC50为200pM。Ceritinib(LDK378)还抑制IGF-1R，InsR和STK22D，IC50值分别为8、7和23nM。Ceritinib(LDK378)显⽰出良好抗肿瘤效⼒。IC50&TargetIC50:0.2nM(ALK),7nM(InsR),8nM(IGF-1R),23nM(STK22D),60nM(FLT3),260nM(FGFR2)[1]体外研究Ceritinib(LDK378)alsoinhibitsRET(IC50=400nM),FGFR3(IC50=430nM),LCK(IC50=560nM),JAK2(IC50=610nM),Aurora(IC50=660nM),LYN(50=840nM),EGFR(IC50=900nM),andFGFR4(IC50=950nM)[1].Ceritinib(LDK378)retainshighpotencyagainsttheALKenzymaticactivitywithanIC50valueof200pMandshowsonlystronginhibitionagainstIGF-1R,InsR,andSTK22Doutofapanelof46kinaseswithaminimumselectivityof70-fold.InBa/F3cellstransfectedwithvariouskinases,CeritinibinhibitsALKactivitywithanIC50valueof40.7nMandhadIC50valuesof>100nMagainstallotherkinasestested.Ceritinib(LDK378)showspotentantiproliferativeactivitywithanIC50valueof22.8nMinKarpas299humannon-Hodgkin’sKi-positivelargecelllymphomacarryingtheNPM-ALKfusiongeneand26nMinBa/F3cellstransfectedwiththeNPM-ALKfusiongene.Ceritinibalsoshowsgoodselectivityoverwild-typeBa/F3cells(IC50>2μM)andBa/F3cellstransfectedwithTel-InsRgene(IC50=320nM)[2].体内研究Ceritinib(LDK378)hasanexcellentpharmacokineticsprofileinrodentsandnon-rodentswithanoralbioavailabilityof>50%.Ceritinibdemonstratesdose-dependenttumorgrowthinhibitionandachievedpartialtumorregressionintheKarpas299ratxenograftmodelwithdailyadministrationbutiscapableofachievingcompletetumorregressionintheH2228NSCLCratxenograftmodel,whichcarriestheEML4-ALKfusiongene.Inbothmodels,Ceritinib(LDK378)iswelltoleratedinanimals.Ceritinib(LDK378)isfurtherassessedforitsADMEprofileandisfoundtohavearelativelygoodmetabolicstabilityinlivermicrosomes,modestCYP3A4inhibition,somehERGinhibitionwithanIC50valueof46μMinhERGpatchclampexperiments,butnoevidenceofQTcprolongationinbothdogandmonkeytelemetrystudies[2].PROTOCOLAnimalInvivoPKstudiesareconductedinmice,rats,dogs,andcynomolgusmonkeys.Ceritinib(LDK378)(HClsalt)Administration[1]isadministeredtomaleBalb/cmiceintravenouslyviatailveinat5mg/kg(n=3)andorallyviagavageat20mg/kg(n=3).Byuseofthesameformulation,Ceritinib(LDK378)(HClsalt)isdosedtoSprague-Dawleyratsintravenouslyviathetailveinat3mg/kg(n=3)andorallyviagavageat10mg/kg(n=3).Bloodsamplesare2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEcollectedseriallyatscheduledtimesover24hafterdosing.Malebeagledogsreceiveasingleintravenous(n=2)ororal(n=3)doseofCeritinib(phosphatesalt)asanintravenoussolutionat5mg/kgandanoralsuspensionat20mg/kg,respectively.Malecynomologusmonkeysreceivesingleintravenous(n=2)ororal(n=3)doseofCeritinib(freebase)asanintravenoussolutionat5mg/kgandanoralsuspensionat60mg/kg,respectively.Bloodsamplesforplasmaarecollectedatprescheduledtimesover144hafterdosing[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•Science.2017Dec1;358(6367):eaan4368.•CellDiscov.2021May11;7(1):33.•NatCancer.2022Oct;3(10):1211-1227.•SciTranslMed.2018Jul18;10(450).pii:eaaq1093.•SciSignal.2015Dec8;8(406):ra125.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].MarsiljeTH,etal.Synthesis,structure-activityrelationships,andinvivoefficacyofthenovelpotentandselectiveanaplasticlymphomakinase(ALK)inhibitor5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine(LDK378)currentlyinphase1andphase2clinicaltrials.JMedChem.2013Jul25;56(14):5675-90.[2].ChenJ,etal.LDK378:apromisinganaplasticlymphomakinase(ALK)inhibitor.JMedChem.2013Jul25;56(14):5673-4.[3].TuckerER,etal.ImmunoassaysforthequantificationofALKandphosphorylatedALKsupporttheevaluationofon-targetALKinhibitorsinneuroblastoma.MolOncol.2017Aug;11(8):996-1006.[4].RothschildSI.Ceritinib-asecond-generationALKinhibitorovercomingresistanceinALK-rearra