Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemECeritinibCat.No.:HY-15656CASNo.:1032900-25-6Synonyms:LDK378分?式:C??H??ClN?O?S分?量:558.14作?靶點:Anaplasticlymphomakinase(ALK);InsulinReceptor;IGF-1R作?通路:ProteinTyrosineKinase/RTK儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數據體外實驗DMSO:5.6mg/mL(10.03mM;Needultrasonic)Ethanol:≥3.33mg/mL(5.97mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM1.7917mL8.9583mL17.9167mL5mM0.3583mL1.7917mL3.5833mL10mM0.1792mL0.8958mL1.7917mL請根據產品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內使?，-20°C儲存時，請在1個?內使?。體內實驗請根據您的實驗動物和給藥?式選擇適當的溶解?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結果的可靠性，澄的儲備液可以根據儲存條件，適當保存；體內實驗的?作液，建議您現?現配，當天使?；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?；如在配制過程中出現沉淀1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE、析出現象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥0.5mg/mL(0.90mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥0.5mg/mL(0.90mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥0.5mg/mL(0.90mM);ClearsolutionBIOLOGICALACTIVITY?物活性Ceritinib(LDK378)?種選擇性，具有?服活性的且具有ATP競爭性的ALK酪氨酸激酶抑制劑，IC50為200pM。Ceritinib(LDK378)還抑制IGF-1R，InsR和STK22D，IC50值分別為8、7和23nM。Ceritinib(LDK378)顯?出良好抗腫瘤效?。IC50&TargetIC50:0.2nM(ALK),7nM(InsR),8nM(IGF-1R),23nM(STK22D),60nM(FLT3),260nM(FGFR2)[1]體外研究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].體內研究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?邊的抑制劑?師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.戶使?本產品發表的科研?獻?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