GZD856-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEGZD856Cat.No.:HY-101489CASNo.:1257628-64-0分⼦式:C₂₉H₂₇F₃N₆O分⼦量:532.56作⽤靶点:PDGFR;Bcr-Abl;Apoptosis作⽤通路:ProteinTyrosineKinase/RTK;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.溶解性数据体外实验DMSO:250mg/mL(469.43mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.8777mL9.3886mL18.7772mL5mM0.3755mL1.8777mL3.7554mL10mM0.1878mL0.9389mL1.8777mL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.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.08mg/mL(3.91mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(3.91mM);ClearsolutionBIOLOGICALACTIVITY1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE⽣物活性GZD856⼀种有效的和具有⼝服活性的PDGFRα/β抑制剂，IC50值分别为68.6和136.6nM。GZD856也是Bcr-AblT315I的抑制剂，对天然Bcr-Abl和T315I突变型的IC50值分别为19.9和15.4nM。GZD856具有抗肿瘤活性。IC50&TargetPDGFRαPDGFRβBcr-AblT315IBcr-Abl68.6nM(IC50)136.6nM(IC50)15.4nM(IC50)19.9nM(IC50)体外研究GZD856(0.0032-10μM,72h)exertsantiproliferativeactivityagainstapaneloflungcancercells[1].GZD856(0.3-3μM;24-28h)inducesadose-dependentG0/G1phasearrestandapoptosisinH1703butnotA549cells[1].GZD856(0.1-10μM;6h)dose-dependentlyinhibitsthePDGFRα/βphosphorylationanddownstreamsignalinginH1703andA549cells[1].GZD856inhibitstheproliferationofK562,K562R(Q252H)andmurineBa/F3cellsectopicallyexpressingBcr-AblWTandBcr-AblT315I,withIC50sof2.2,67.0,0.64and10.8ꢀnM,respectively[2].CellViabilityAssay[1]CellLine:H1703,A549,Calu-6,95-D,L-78,HCC827,SPCA-1,H1650,H1299,H522,H332andH820NSCLCcellsConcentration:0.0032-10μMIncubationTime:72hoursResult:InhibitedPDGFRα-overexpressingH1703cells,withanIC50of0.25μM.ApoptosisAnalysis[1]CellLine:H1703andA549NSCLCcellsConcentration:0.3,1,3μMIncubationTime:24,48hoursResult:Ledto54.1%apoptosisinH1703cellsattheconcentrationof3.0ꢀµM,whereasonly15.5%apoptoticA549cellswereobservedundersimilarconditions.DecreasedtheCDK4,cyclinD2,CDK2andCyclinEproteinlevelsandactivatedofPARPandCaspase-3cleavageinH1703cells.WesternBlotAnalysis[1]CellLine:H1703andA549NSCLCcellsConcentration:0.1-10μMIncubationTime:6hoursResult:InhibitedthephosphorylationofPDGFRαandPDGFRβinadose-dependentmanner.2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEObservedtheactivationofdownstreamAKT,ERK1/2andSTAT3,withnoobviouseffectsontotalproteinlevels.体内研究GZD856(10-30mg/kg,p.o.oncedailyfor16d)displaysgoodantitumoractivityinbothH1703andA549lungcancermodelsandiswelltolerated.GZD856inhibitsbrainandlivermetastasisoflungcancercellsinanA549-Lucorthotopicmodel[1].GZD856(10ꢀmg/kg;p.o.oncedailyfor8d)potentlyinhibitstumorgrowthinmousebearingxenograftK562andBa/F3cellsexpressingBcr-AblT315I[2].GZD856(5mg/kg;asinglei.v.)exhibitsalonghalf-life(T1/2=19.97h),optimalplasmaexposure(Cmax=934.38μg/L)andaAUC0-∞(8165.8µg/L•h)inrats[1].GZD856(25mg/kg;asinglep.o.)exhibitsalonghalf-life(T1/2=22.2h),optimalplasmaexposure(Cmax=899.5μg/L)andagoodoralbioavailability(BA=78%)inrats[1].AnimalModel:MaleCB17-SCIDmiceimplantedwithH1703andA549cancercells[1]Dosage:10,30mg/kgAdministration:Oralgavageoncedailyfor16daysResult:DisplayedantitumoreffectsinH1703-xenograftmice,withtumorgrowthinhibition(TGI)valuesof20.8%and74.1%atdosagesof10and30mg/kg,respectively.DisplayedantitumoreffectsinA549-xenograftmice,withaTGIvalueof51.1%at30mg/kg.Waswelltoleratedinallofthetestedgroups,withnomortalityorsignificantlossofbodyweight.AnimalModel:Sprague-Dawley(SD)rats(180-220ꢀg)[1]Dosage:5mg/kgfori.v.;25mg/kgforp.o.(PharmacokineticAnalysis)Administration:AsingleintravenousinjectionandoraladministrationResult:I.v.:T1/2=19.97h;Cmax=934.38μg/L;AUC0-∞=8165.8µg/L•h.P.o.:T1/2=22.2h;Cmax=899.5μg/L;BA=78%.REFERENCES[1].ZhangZ,etal.GZD856,anovelpotentPDGFRα/βinhibitor,suppressesthegrowthandmigrationoflungcancercellsinvitroandinvivo.CancerLett.2016May28;375(1):172-178.[2].LuX,etal.SynthesisandidentificationofGZD856asanorallybioavailableBcr-AblT315Iinhibitorovercomingacquiredimatinibresistance.JEnzymeInhibMedChem.2017Dec;32(1):331-336.McePdfHeight3/3MasterofB