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Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemENVP-CGM097sulfateCat.No.:HY-15954BCASNo.:1313367-56-4Synonyms:CGM097sulfate分⼦式:C₃₈H₄₉ClN₄O₈S分⼦量:757.34作⽤靶点:MDM-2/p53;E1/E2/E3Enzyme作⽤通路:Apoptosis;MetabolicEnzyme/Protease储存⽅式:4°C,sealedstorage,awayfrommoisture*Insolvent:-80°C,6months;-20°C,1month(sealed

storage,awayfrommoisture)溶解性数据体外实验DMSO:100mg/mL(132.04mM;Needultrasonic)H2O:100mg/mL(132.04mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.3204mL6.6021mL13.2041mL5mM0.2641mL1.3204mL2.6408mL10mM0.1320mL0.6602mL1.3204mL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(sealedstorage,awayfrommoisture)。-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:≥2.5mg/mL(3.30mM);Clearsolution2.请依序添加每种溶剂:10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(3.30mM);Clearsolution3.请依序添加每种溶剂:10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(3.30mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性NVP-CGM097有效,选择性的MDM2抑制剂;IC50值为1.7nM。IC50&TargetIC50&Target:IC50:1.7±0.1nM(hMDM2)[1]体外研究NVP-CGM097bindstohumanMDM2withanIC50of1.7nMandshowshighselectivityoverMDM4(IC50=2000nM).NVP-CGM097isaboutfourtimesmorepotentthanNutlin-3a(IC50=8nM).Inaddition,NVP-CGM097showsnosignificantactivityagainstBcl-2:Bak,Bcl-2:Bad,Mcl-1:Bak,Mcl-1:NOXA,XIAP:BIR3,andc-IAP:BIR3protein-proteininteractions.NVP-CGM097significantlyinhibitstheproliferationofcellsexpressingwild-typep53,whilesparingthep53nullcellswitha35-58-folddifference.NVP-CGM097isabletosignificantlyredistributewild-typep53intothecellnucleuswithanIC50of0.224μM,demonstratingitsabilitytoinhibitthep53:MDM2interactioninlivingcells.NVP-CGM097significantlyinhibitstheproliferationofcellsexpressingwild-typep53,whilesparingthep53nullcellswitha35-58-folddifference.NVP-CGM097inhibtisHCT116(p53WT/WT)withIC50of454±136nM[1].体内研究NVP-CGM097isabletoinhibittheinteractionbetweenp53andMDM2andreactivatethep53pathwayinaMDM2-amplifiedSJSA-1humantumormodel,asjudgedbyelevationofp21mRNAlevels,apharmacodynamic(PD)indicatorforp53activity.p21mRNAlevelsarefoundtoincreaseconcomitantlywithlevelsofNVP-CGM097intumor-bearingratsdosedat30mg/kg.ThePDresponseisbiphasicandprolongedupto24h.Additionalp53targetgenessuchasMDM2andPUMAmRNAlevelsareassessedinthetumorsamplesaswellandshowedasimilarbehavior.DailytreatmentwithNVP-CGM097dosedependentlyandsignificantlyinhibitsSJSA-1tumorgrowthinrats.Itpromotesstablediseaseat20mg/kg,whichisassociatedwithaplasmaAUC0-24of163μM•h.Afterivadministration,thetotalbloodclearance(CL)ofNVP-CGM097is5mL/minperkgformouse,7mL/minperkgforrat,3mL/minperkgfordog,and4mL/minperkgformonkey.Theapparentterminalhalf-life(t1/2)islonginrodentsandmonkey(6-12h)butiscomparativelylongerindogs(20h).Afteroraldosing,NVP-CGM097iswellabsorbedwithTmaxoccurringbetween1and4.5hinallspeciestested[1].PROTOCOLCellAssay[1]TwopairsofcelllinesareusedtoassessNVP-CGM097p53-dependentantiproliferativeeffects:(1)anisogenicpairofHCT116celllineseitherexpressingwild-typep53orknocked-outforthep53geneand(2)anonisogenicpairofosteosarcomacelllineseitherendogenouslyexpressingwild-typep53andamplifiedforMDM2(SJSA-1cells)ornullforp53(SAOS-2cells)[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAnimalFemaleathymicratsbearingsubcutaneousxenotransplantsofSJSA-1tumors(n=5-12)aretreatedat5,10,Administration[1]20,or30mg/kgorthreetimesaweekonMonday,Wednesday,andFriday(3qwM,W,F)at30or70mg/kgpofor14days.PlasmaAUCsaredeterminedattheendofthestudy.Positivenumbersindicatethepercentageoftumorgrowthinhibition(T/C);negativenumbersindicatethepercentageoftumorregression[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].HolzerP,etal.DiscoveryofaDihydroisoquinolinoneDerivative(NVP-CGM097):AHighlyPotentandSelectiveMDM2InhibitorUndergoingPhase1ClinicalTrialsinp53wtTumors.JMedC

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