Navoximod-GDC-0919-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemENavoximodCat.No.:HY-18770BCASNo.:1402837-78-8Synonyms:GDC-0919;NLG-919分⼦式:C₁₈H₂₁FN₂O₂分⼦量:316.37作⽤靶点:Indoleamine2,3-Dioxygenase(IDO)作⽤通路:MetabolicEnzyme/Protease储存⽅式:-20°C,storedundernitrogen*Insolvent:-80°C,6months;-20°C,1month(storedunder

nitrogen)溶解性数据体外实验DMSO:100mg/mL(316.09mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM3.1609mL15.8043mL31.6086mL5mM0.6322mL3.1609mL6.3217mL10mM0.3161mL1.5804mL3.1609mL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(storedundernitrogen)。-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：1%DMSO>>99%salineSolubility:≥0.5mg/mL(1.58mM);Clearsolution1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE2.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥3mg/mL(9.48mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥3mg/mL(9.48mM);Clearsolution4.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥3mg/mL(9.48mM);Clearsolution5.请依序添加每种溶剂：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(7.90mM);Clearsolution6.请依序添加每种溶剂：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(7.90mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Navoximod(GDC-0919;NLG-919)⼀种有效的IDO(indoleamine-(2,3)-dioxygenase)抑制剂，Ki/EC50分别为7nM/75nM。IC50&TargetIDOIDO75nM(EC50)7nM(Ki)体外研究UsingIDO-expressinghumanmonocyte-deriveddendriticcells(DCs)inallogeneicmixedlymphocytereaction(MLR)reactions,Navoximod(NLG919)potentlyblocksIDO-inducedTcellsuppressionandrestoresrobustTcellresponseswithanED50=80nM.Similarly,usingIDO-expressingmouseDCsfromtumor-draininglymphnodes,NavoximodabrogatesIDO-inducedsuppressionofantigen-specificTcells(OT-I)invitro,withED50=120nM[1].NavoximodinhibitstheIDOactivityinaconcentration-dependentmannerwithanEC50of0.95ꢀμM.PEG2k-Fmoc-NLG(L)islessactive(EC50of3.4ꢀμM)ininhibitingIDOcomparedwithfreeNavoximodwhilePEG2k-Fmoc-NLG(S)isleastactive(EC50>10ꢀμM).CocultureofIDO+tumorcellswithsplenocytesisolatedfromBALB/cmiceleadstosignificantinhibitionofT-cellproliferation.ThisinhibitionissignificantlyattenuatedwhenthemixedcellsaretreatedwithNavoximod.PEG2k-Fmoc-NLG(L)isalsoactiveinreversingtheinhibitoryeffectoftumourcellsalthoughslightlylesspotentthanNavoximod[3].体内研究VNavoximod(NLG919)isorallybioavailable(F>70%);andhasafavorablepharmacokineticandtoxicityprofile.Inmice,asingleoraladministrationofNavoximodreducestheconcentrationofplasmaandtissueKynby~50%.Invivo,inmicebearinglargeestablishedB16F10tumors,administrationofNavoximodmarkedlyenhancestheanti-tumorresponsesofnaïve,restingpmel-1cellstovaccinationwithcognatehgp100peptideplusCpG-1826inIFA.Inthisstringentestablished-tumormodel,Navoximodpluspmel-1/vaccineproduceadramaticcollapseoftumorsizewithin4daysofvaccination(~95%reductionintumorvolumecomparetocontrolanimalsreceivingpmel-1/vaccinealonewithoutNavoximod)[1].WhencombinedwithNSC362856(TMZ)+radiationtherapy(RT),bothNavoximodandD-1MT(Indoximod)enhancesurvivalrelativetomicetreatedwithTMZ+RTalone[2].PROTOCOL2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellAssay[3]TheIDOinhibitoryeffectofPEG2k-Fmoc-NLGistestedbyaninvitroIDOassay.Briefly,HeLacellsareseededina96-wellplateatacelldensityof5000cellsperwellandallowedtogrowovernight.RecombinanthumanIFN-γisthenaddedtoeachwellwithafinalconcentrationof50ꢀng/mL.Atthesametime,variousconcentrationsofPEG2k-Fmoc-NLG(L),PEG2k-Fmoc-NLG(S)orNavoximod(NLG919)(50ꢀnM-20ꢀμM)areaddedtothecells.After48ꢀhofincubation,150ꢀμLofthesupernatantsperwellistransferredtoanew96-wellplate.Seventy-fiveμLof30%trichloroaceticacidisaddedintoeachwellandthemixtureisincubatedat50°Cfor30ꢀmintohydrolyseN-formylkynureninetokynurenine.Forcolorimetricassay,supernatantsaretransferredtoanew96-wellplate,mixedwithequalvolumeofEhrlichreagent(2%p-dimethylamino-benzaldehydew/vinglacialaceticacid),andincubatedfor10ꢀminatRT.Reactionproductismeasuredat490ꢀnmbyaplatereader[3].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[2]Administration[2]Miceareimmobilizedinastereotacticframefortumorimplantation.Briefly,theskullisshavedandexposedwitha0.5cmskinincision.Withantiseptictechnique,105GL261cells(suspendedin3μLRPMI-1640)areinjectedatthefollowingcoordinateswithrespecttothebregmaontherightside(antero-posterior,-2mm;medio-lateral,2mm;dorso-ventral,3mm).Thisplacementreproduciblyyieldedtumorgrowthinaparacorticalareaoftheposterolateralrightfrontallobe.Tumor-bearingmicearetreatedwithcombinationsoforalDL-1MT(2mg/mLD-1MTmixedwith2mg/mLL-1MT)indrinkingwater,D-1MT(4mg/mL)indrinkingwater,Navoximod(6mg/mL)indrinkingwater,intraperitonealNSC-26271,intraperitonealNSC362856,and/ortotal-bodyradiation(500cGyfroma137Cssource),asdetailedinfigurelegends.Miceareobserveddaily,andsacrificedwhentheybecameillormoribund[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•NanoToday.October2022,101600.•NatCommun.2022Jul12;13(1):4032.•AdvSci(Weinh).2019Apr18;6(12):1900327.•ToxicolApplPharmacol.2017May15;323:74-80.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].MarioR.Mautino,etal.Abstract491:NLG919,anovelindoleamine-2,3-dioxygenase(IDO)-pathwayinhibitordrugca