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Medchemexpress/MLN4924(Synonyms: Pevonedistat)/HY-70062/1mg
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Medchemexpress/MLN4924(Synonyms: Pevonedistat)/HY-70062/1mg
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HY-70062-10mM*1mLinDMSO
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MLN4924isapotentandselectiveNEDD8-activatingenzyme(NAE)inhibitorwithIC50of4.7nM.

CustomerValidation

  • •NatCommun.2017May22;8:15398.
  • •Elife.2016Apr11;5.pii:e14087.
  • •Oncotarget.2017Sep23;8(49):86395-86409.
  • •Oncotarget.2016Oct4;7(40):66087-66099.
  • •Oncotarget.2016Jun14;7(24):35643-35654.
  • •AmJPhysiolLungCellMolPhysiol.2017Jul1;313(1):L104-L114.
  • •Virology.2015Mar;477:10-7.
  • •AnnHematol.2014Sep;93(9):1499-508.
  • •BiochemBiophysResCommun.2017Jan29;483(1):223-229.
  • •TechnolCancerResTreat.2016Aug;15(4):527-34.
  • •UlmUniversity.13-01-2017.
Description

MLN4924isapotentandselectiveNEDD8-activatingenzyme(NAE)inhibitorwithIC50of4.7nM.

IC50&Target

IC50:4.7nM(NAE)[1]

InVitro

MLN4924isapotentinhibitorofNAE,andisselectiverelativetothecloselyrelatedenzymesUAE,SAE,UBA6andATG7(IC50=1.5,8.2,1.8and>10μM,respectively)whenevaluatedinpurifiedenzymeassaysthatmonitortheformationofE2-UBLthioesterreactionproducts.MLN4924selectivelyinhibitsNAEactivitycomparedtothecloselyrelatedubiquitin-activatingenzyme(UAE,alsoknownasUBA1)andSUMO-activatingenzyme(SAE;aheterodimerofSAE1andUBA2subunits),inpurifiedenzymeandcellularassays.MLN4924exhibitspotentcytotoxicactivityagainstavarietyofhumantumour-derivedcelllines[1].

InVivo

MLN4924(sc,10mg/kg,30mg/kg,or60mg/kg)inhibitstheNEDD8pathwayresultinginDNAdamageinMicebearingHCT-116xenografts[1].Pevonedistat(sc,120mg/kg)andTNF-α(10μg/kg)synergisticallycauseliverdamageinSDrats[2].

ClinicalTrial
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References

  • [1].SoucyTA,etal.AninhibitorofNEDD8-activatingenzymeasanewapproachtotreatcancer.Nature.2009Apr9;458(7239):732-6.

    [2].FSWolenski,etal.TheNAEinhibitorpevonedistat(MLN4924)synergizeswithTNF-αtoactivateapoptosis.CellDeathDiscovery1,Articlenumber:15034(2015)

PreparingStockSolutions
ConcentrationVolumeMass1mg5mg10mg
1mM2.2547mL11.2734mL22.5469mL
5mM0.4509mL2.2547mL4.5094mL
10mM0.2255mL1.1273mL2.2547mL
Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.
CellAssay
[1]

MLN4924isdissolvedinDMSOandstored,andthendilutedwithappropriatemediumbeforeuse[1].

HCT-116cellsgrownin6-wellcell-culturedishesaretreatedwith0.1%DMSO(control)or0.3μMMLN4924for24h.Wholecellextractsarepreparedandanalysedbyimmunoblotting.ForanalysisoftheE2-UBLthioesterlevels,lysatesarefractionatedbynon-reducingSDS-PAGEandimmunoblottedwithpolyclonalantibodiestoUbc12,Ubc9andUbc10.Foranalysisofotherproteins,lysatesarefractionatedbyreducingSDS-PAGEandprobedwithprimaryantibodiesasfollows:mousemonoclonalantibodiestoCDT1,p27,geminin,ubiquitin,securin/PTTGandp53orrabbitpolyclonalantibodiestoNRF2,CyclinB1andGADD34[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdmiNISTration
[1][2]

MLN4924isdissolvedinDMSOandthendilutedwithPBSorsaline.

Mice[1]
MicebearingHCT-116tumoursof300-500mm3areadministeredasingleMLN4924dose(of10,30or60mg/kg),andtumorsareexcisedatvarioustime-pointsoverthesubsequent24hperiod.TherelativelevelsofNEDD8-cullinandNRF2areestimatedbyquantitativeimmunoblotanalysisusingAlexa680-labelledanti-IgGasthesecondaryantibody.ThestatisticaldifferencebetweenthegroupsforNEDD8-cullininhibitionisdeterminedusingtheKruskal-Wallistest.FortheanalysisofCDT1andphosphorylatedCHK1(Ser317)levelsintumoursections,formalin-fixed,paraffin-embeddedtumoursectionsarestainedwiththerelevantantibodies,amplifiedwithHRP-labelledsecondaryantibodiesanddetectedwiththeChromoMapDABKit.Slidesarecounterstainedwithhaematoxylin.ImagesarecapturedusinganEclipseE800microscopeandRetigaEXicolourdigitalcameraandprocessedusingMetamorphsoftware.CDT1andphosphorylatedCHK1levelsareexpressedasafunctionoftheDABsignalarea.
Rat[2]
Ten-week-oldmaleSprague-Dawleyratsareused.Acrosstwostudies,atotalofeightanimalsineachgrouparedosedwithvehicle,TNF-α,MLN4924,orMLN4924+TNF-α.Animalsarefirstintravenouslyadministeredeithervehicle(1×PBS)or10μg/kgTNF-α.Onehourlater,theyaresubcutaneouslyadministeredvehicle(20%sulfobutyletherbeta-cyclodextrinin50mMcitratebuffer,pH3.3)or120mg/kgMLN4924.Scheduledeuthanasiaoccurred24hpostdose.Unscheduledeuthanasiaisperformedwhenanimalsexhibitedmoribundconditions.SerumiscollectedatnecropsyandanalyzedbyIdexxLaboratoriesforserumchemistryMarkersofliverdamage.Additionally,theliversfromfiveanimalsineachgroupareremoved,separatedintotwosectionsandeitherfrozenat-80°Cforsubsequentproteinanalysisorfixedin10%neutralbufferedformalin,embeddedinparaffin,sectionedat4-6μm,mountedonglassslides,stainedwithhematoxylinandeosin,andanalyzedwithanOlympusBX51lightmicroscopeforhistopathologyassessment.Microscopicfindingsarerecordedinconcordancewiththestandardizednomenclatureforclassifyinglesionswithintheliversofrats.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

  • [1].SoucyTA,etal.AninhibitorofNEDD8-activatingenzymeasanewapproachtotreatcancer.Nature.2009Apr9;458(7239):732-6.

    [2].FSWolenski,etal.TheNAEinhibitorpevonedistat(MLN4924)synergizeswithTNF-αtoactivateapoptosis.CellDeathDiscovery1,Articlenumber:15034(2015)

MolecularWeight

443.52

Formula

C₂₁H₂₅N₅O₄S

CASNo.

905579-51-3

Storage
Powder-20°C3years
 4°C2years
Insolvent-80°C6months
 -20°C1month
Shipping

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

DMSO:≥111.25mg/mL

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

Purity:98.00%

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