AZD8186-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEAZD8186Cat.No.:HY-12330CASNo.:1627494-13-6分⼦式:C₂₄H₂₅F₂N₃O₄分⼦量:457.47作⽤靶点:PI3K作⽤通路:PI3K/Akt/mTOR储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:≥35mg/mL(76.51mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM2.1859mL10.9297mL21.8594mL5mM0.4372mL2.1859mL4.3719mL10mM0.2186mL1.0930mL2.1859mL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.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.08mg/mL(4.55mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(4.55mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(4.55mM);Clearsolution4.请依序添加每种溶剂：10%DMSO/60%tri-ethyleneglycol(TEG)/30%waterSolubility:15mg/mL(32.79mM);Clearsolution;Needultrasonic5.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.75mg/mL(6.01mM);Clearsolution6.请依序添加每种溶剂：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:≥2.75mg/mL(6.01mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性AZD8186⼀种PI3K抑制剂，抑制PI3Kβ(IC5050=4nM)，PI3Kδ(IC5050=12nM)，PI3Kα(IC50=35nM)和PI3Kγ(IC50=675nM)。IC50&TargetPI3KβPI3KδPI3KαPI3Kγ4nM(IC50)12nM(IC50)35nM(IC50)675nM(IC50)体外研究AZD8186isapotentinhibitorofPI3KβwithadditionalactivityversusthePI3Kδisoform.Tight-bindingkineticsofAZD8186meansbiochemicalassaysunderestimatetheabsoluteselectivityprofileforPI3Ks.InabroadpanelofproteinandlipidkinaseassaysselectivityforPI3Kβandδis>100-foldversus74proteinandlipidkinases.At10μM,AZD8186hadnosignificantbindingto442otherkinasesinaKinomeScanscreen.AZD8186showsselectivityforPI3Kfamilykinases,nootheroff-targetactivityisdetected.InthePTEN-nullline,MDA-MB-468AZD8186inhibitsPI3Kβ-dependentactivationofpAKT(Ser473)withanIC50valueof3nM.PotencyinthePIK3CA-mutantlineBT474cis752nMdemonstratingselectivityforPI3KβoverPI3Kα.IgMmediatedstimulationofBcellsresultsinphosphorylationofAKTthroughactivationofPI3Kδ.AZD8186inhibitsIgM-stimulatedphosphorylationofpAKT(Ser473)activationinJEKOcellswithanIC50valueof17nM.Incellproliferationassays,AZD8186inhibitsproliferationofMDA-MB-468cellswithaGI50valueof65nM,IgMstimulatedJEKOcellgrowthwithanIC50valueof228nM.ItonlyinhibitedBT474ccellgrowthwithanIC50valueof1.981μMconsistentwithitsselectivityforPI3KβoverPI3Kα[1].体内研究Toassesssingle-agentefficacyofAZD8186invivo,antitumoractivityisassessedinthePTEN-nullTNBCmodelsHCC70andMDA-MB-468,andtheprostatemodelsPC3andHID28.At50and25mg/kgtwiceaday,AZD8186inhibitsthegrowthofallfourmodels.At25and50mg/kg,HCC70isinhibitedat62%(P[1].PROTOCOLCellAssay[1]CellsareexposedtoAZD8186atconcentrationsrangingfrom3to0.01μMfor2hours.Cellsarethenlysedonicewithabuffercontaining25mMTris/HCLpH6.8,3mMEDTA,3mMEGTA,50mMNaF,2mMsodiumorthovanadate,270mMsucrose,10mMβ-glycerophosphate,5mMsodiumpyrophosphate,and0.5%Triton2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEX-100andproteaseandphosphataseinhibitors.Lysatesaredilutedwithsampleloadingbuffer,separatedon4%to12%Bis-TrisNovexgels,transferredontonitrocellulosemembranes,andprobedwithprimaryantibodiesovernight.Afterawashingstep,membranesareincubatedwithHRP-taggedsecondaryantibodiesandvisualized[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[1]Administration[1]ThefemaleCB17SCIDmiceages6to8weeksareused.HID28invivoexperimentsareperformedundercontractbyXentech,HID28tumorfragments(approximately40mm3)fromdonoranimalsareasepticallyimplantedsubcutaneouslyinattheleveloftheinterscapularregion.Outbredathymic(nu/nu)malemice(HSD:AthymicNude-Foxn1nu)weighing18to25g.Forallanimalsstudiesgroupsarepoweredwithaminimumof8animalspergroup.AZD8186isgenerallyformulatedonceweeklyasasuspensioninHPMC/Tweenanddosedonceortwicedaily(0and6-8hours).AZD8186isformulatedonceweeklyeitheralonein10%DMSO/60%tri-ethyleneglycol(TEG)/30%waterforinjection(WFI)orinthepresenceofABTat10mg/mL.Fortwicedailydosing(0and6-8hours),AZD8186isco-dosedwithABTat0hoursandadministeredaloneasthesingleformulationat6to8hours.RP-56976isformulatedfreshinphysiologicsalineat1.5mg/mLanddosedasasinglei.v.bolusdoseatarateof0.1mL/10gonday0,24hoursbeforetheadministrationofAZD8186.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•Blood.2019Jan3;133(1):70-80.•SciTranslMed.2018Jul18;10(450).pii:eaaq1093.•Diabetes.2021Oct21;db210240.•Oncotarget.2020Nov3;11(44):3921-3932.•bioRxiv.2019Oct.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].HancoxU,etal.InhibitionofPI3KβsignalingwithAZD8186inhibitsgrowthofPTEN-deficientbreastandprostatetumorsa