Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEGZD856Cat.No.:HY-101489CASNo.:1257628-64-0分?式:C??H??F?N?O分?量:532.56作?靶點(diǎn):PDGFR;Bcr-Abl;Apoptosis作?通路:ProteinTyrosineKinase/RTK;Apoptosis儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:250mg/mL(469.43mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM1.8777mL9.3886mL18.7772mL5mM0.3755mL1.8777mL3.7554mL10mM0.1878mL0.9389mL1.8777mL體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)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(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.08mg/mL(3.91mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(3.91mM);ClearsolutionBIOLOGICALACTIVITY1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE?物活性GZD856?種有效的和具有?服活性的PDGFRα/β抑制劑，IC50值分別為68.6和136.6nM。GZD856也是Bcr-AblT315I的抑制劑，對(duì)天然Bcr-Abl和T315I突變型的IC50值分別為19.9和15.4nM。GZD856具有抗腫瘤活性。IC50&TargetPDGFRαPDGFRβBcr-AblT315IBcr-Abl68.6nM(IC50)136.6nM(IC50)15.4nM(IC50)19.9nM(IC50)體外研究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,withIC50sof2.2,67.0,0.64and10.8?nM,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%apoptosisinH1703cellsattheconcentrationof3.0?μM,whereasonly15.5%apoptoticA549cellswereobservedundersimilarconditions.DecreasedtheCDK4,cyclinD2,CDK2andCyclinEproteinlevelsandactivatedofPARPandCaspase-3cleavageinH1703cells.WesternBlotAnalysis[1]CellLine:H1703andA549NSCLCcellsConcentration:0.1-10μMIncubationTime:6hoursResult:InhibitedthephosphorylationofPDGFRαandPDGFRβinadose-dependentmanner.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEObservedtheactivationofdownstreamAKT,ERK1/2andSTAT3,withnoobviouseffectsontotalproteinlevels.體內(nèi)研究GZD856(10-30mg/kg,p.o.oncedailyfor16d)displaysgoodantitumoractivityinbothH1703andA549lungcancermodelsandiswelltolerated.GZD856inhibitsbrainandlivermetastasisoflungcancercellsinanA549-Lucorthotopicmodel[1].GZD856(10?mg/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(180-220?g)[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