AZD8186-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEAZD8186Cat.No.:HY-12330CASNo.:1627494-13-6分?式:C??H??F?N?O?分?量:457.47作?靶點:PI3K作?通路:PI3K/Akt/mTOR儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:≥35mg/mL(76.51mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.1859mL10.9297mL21.8594mL5mM0.4372mL2.1859mL4.3719mL10mM0.2186mL1.0930mL2.1859mL請根據(jù)產(chǎn)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(fù)凍融造成的產(chǎn)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(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當?shù)娜芙?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(jié)果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)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(xiàn)沉淀、析出現(xiàn)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%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.08mg/mL(4.55mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(4.55mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(4.55mM);Clearsolution4.請依序添加每種溶劑：10%DMSO/60%tri-ethyleneglycol(TEG)/30%waterSolubility:15mg/mL(32.79mM);Clearsolution;Needultrasonic5.請依序添加每種溶劑：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.75mg/mL(6.01mM);Clearsolution6.請依序添加每種溶劑：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:≥2.75mg/mL(6.01mM);ClearsolutionBIOLOGICALACTIVITY?物活性AZD8186?種PI3K抑制劑，抑制PI3Kβ(IC5050=4nM)，PI3Kδ(IC5050=12nM)，PI3Kα(IC50=35nM)和PI3Kγ(IC50=675nM)。IC50&TargetPI3KβPI3KδPI3KαPI3Kγ4nM(IC50)12nM(IC50)35nM(IC50)675nM(IC50)體外研究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].體內(nèi)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?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻?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