Zorifertinib-AZD3759-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEZorifertinibCat.No.:HY-18750CASNo.:1626387-80-1Synonyms:AZD3759分⼦式:C₂₂H₂₃ClFN₅O₃分⼦量:459.9作⽤靶点:EGFR作⽤通路:JAK/STATSignaling;ProteinTyrosineKinase/RTK储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:≥50mg/mL(108.72mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM2.1744mL10.8719mL21.7439mL5mM0.4349mL2.1744mL4.3488mL10mM0.2174mL1.0872mL2.1744mL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)1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(5.44mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(5.44mM);Suspendedsolution;Needultrasonic3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.44mM);Clearsolution4.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(5.44mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Zorifertinib(AZD3759)⼀种有效的，具有⼝服活性的，可渗透中枢神经系统的EGFR抑制剂。作⽤于EGFRwt，EGFRL858R和EGFRexon19Del，IC50分别为0.3，0.2和0.2nM[1]。IC50&TargetEGFREGFRL858REGFRExon19deletion0.3nM(IC50)0.2nM(IC50)0.2nM(IC50)体外研究At2mMofATPconcentrations,theIC50sare102,7.6,and2.4nMforEGFRwt,EGFRL858R,andEGFRexon19Del,respectively.Zorifertinib(AZD3759)alsoinhibitspEGFRinH838wt,H3255L858R,andPC-9exon19DelwithIC50of64.5,7.2,and7.4nM,respectively.Incellularphosphorylationstudies,Zorifertinibalsodemonstrates9-foldinhibitionselectivityinEGFR-activatingmutantcelllinesoverEGFRwild-typecelllines(H838cellline)[1].体内研究Followingoraldosinginratsat2mg/kg,absorptionofZorifertinib(AZD3759)israpidwithbloodCmaxof0.58μMachievedat1.0h.Subsequently,bloodconcentrationsofZorifertinibdeclinemonoexponentiallywithameaneliminationhalf-lifeof4.3h,whichisclosetothesameparameterobtainedfromintravenousdosingof4.1h.Thebioavailabilityfollowinganoraldoseinratsis91%.BloodpharmacokineticparametersofZorifertinibinmaledogsaredeterminedfollowingbothasingledoseintravenousinfusionandoraladministration.FollowingtheIVdoseindogs,Zorifertinibbloodclearanceisdeterminedas14mL/minperkg,andthevolumeofdistributionis6.4L/kg.Itseliminationhalf-lifeis6.2h.AbsorptionofZorifertinibisrapidwithbloodCmax(698nM)occurringbetween0.5and1.5h.TheoralbioavailabilityofZorifertinibisexcellentat90%.Zorifertinibdemonstratedsignificantdose-dependentantitumorefficacy(78%tumorgrowthinhibitionat7.5mg/kgqdandtumorregressionat15mg/kgqd,respectively,4weeksaftertreatment)with[1].PROTOCOLCellAssay[1]CellproliferationassayisdeterminedbyMTSmethods.Briefly,cellsareseededin96-wellplates(atadensitytoallowforlogarithmicgrowthduringthe72-hourassay)andincubatedovernightat37°Cand5%CO2.Cellsarethenexposedtoconcentrationsofcompounds(e.g.,Zorifertinib)rangingfrom30mMto0.3μMfor72hours.FortheMTSendpoint,cellproliferationismeasuredbytheCellTiterAQueousNon-RadioactiveCellProliferationAssayreagent.AbsorbanceismeasuredwithaTecanUltrainstrument.Predosemeasurementsaremade,andconcentrationneededtoreducethegrowthoftreatedcellstohalf2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEthatofuntreatedcells(GI50)valuesaredeterminedusingabsorbancereadings[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalRats[1]Administration[1]MaleHanWistarratsareorallydosedwiththeZorifertinibat2mg/kgin1%methylcellulose.At0.25,0.5,1,2,4and7hourpost-dose,cerebralspinalfluid(CSF)iscollectedfromcisternamagna,andbloodsamples(>60μL/timepoint/eachsite)arecollectedviacardiacpuncture,intoseparateEDTAcoagulatedtubes,andthenimmediatelydilutedwith3-foldvolumeofwater.Braintissueisharvestedandhomogenizedin3xvolumeof100mMphosphatebufferedsaline(pH7.4).Allsamplesarestoredat-70°CpriortoLC/MS/MSanalysis.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•RSCAdv.2022,12,20991-21003.•JPharmBiomedAnal.2022Jan29;211:114626.•Patent.US20220177473A1.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].ZengQ,etal.DiscoveryandEvaluationofClinicalCandidateAZD3759,aPotent,OralActive,CentralNervousSystem-Penetrant,EpidermalGrowthFactorReceptorTyrosineKinaseInhibit