MI-3454-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•Agonists•ScreeningLibrarieswww.MedChemEMI-3454Cat.No.:HY-136360CASNo.:2134169-43-8分⼦式:C₃₂H₃₅F₃N₈OS分⼦量:636.73作⽤靶点:EpigeneticReaderDomain作⽤通路:Epigenetics储存⽅式:4°C,storedundernitrogen*Insolvent:-80°C,6months;-20°C,1month(storedunder

nitrogen)BIOLOGICALACTIVITY⽣物活性MI-3454⼀种具有⼝服活性，⾼效和选择性的Menin-MLL1相互作⽤抑制剂，IC50为0.51nM。MI-3454通过下调涉及⽩⾎病发⽣的关键因，在MLL1重排或NPM1突变的⽩⾎病⼩⿏模型中抑制细胞增殖，诱导分化并完全缓解或消退⽩⾎病。IC50&TargetIC50:0.51nM(menin-MLL1interaction)[1]体外研究MI-3454(0.001-10μM;7days)stronglyreducesmurinebonemarrowcellstransformedwithMLL-AF9orHoxa9/Meis1proliferation[1].MI-3454(50nM;6days)leadstodownregulatedexpressionofHOXA9andMEIS1inHumanleukemiccelllinesMV-4-11cellsorMOLM13[1].MI-3454markedlyreducestheviabilityofleukemiccellsharboringvariousMLLfusionproteins(MLL-AF9,MLL-AF4,MLL-ENL),withGI50valuesrangingfrom7to27nM.MI-3454blockstheinteractionofmeninwithanMLL14–43fragmentencompassingtheentiremeninbindingmotif[1].MI-3454doesnotpotentlyinhibitcytochromesP450([1].CellProliferationAssay[1]CellLine:MurinebonemarrowcellstransformedwithMLL-AF9orHoxa9/Meis1Concentration:0.001,0.01,0.1,1,10μMIncubationTime:7days1/3MasterofSmallMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:Demonstratedstrongreductionofcellproliferation.RT-PCR[1]CellLine:HumanleukemiccelllinesMV-4-11cellsorMOLM13Concentration:50nMIncubationTime:6daysResult:LedtodownregulatedexpressionofHOXA9andMEIS1andexpressionlevelofotherMLLfusiontargetgenes,includingMEF2C,DLX2,HOXA10,PBX3,andFLT3.体内研究MI-3454inducescompleteremissionorregressionofleukemiainmousemodelsofmixedlineageleukemia1(MLL1)-rearrangedornucleophosmin1(NPM1)-mutatedleukemia[1].MI-3454(p.o.;120mg/kg;oneortwicedailyfor7consecutivedays)sufficientlyblocksleukemiaprogressionbyaonce-dailytreatment[1].MI-3454(p.o.;100mg/kg;b.i.d.;for19consecutivedays)effectivelyblocksleukemiaprogressionduringthetreatmentperiodandmarkedlyprolongssurvivalofMOLM13xenotransplantationmodelmice.MI-3454inducescompleteremissionorblocksleukemiaprogressioninpatient-derivedxenograft(PDX)modelsofMLLleukemia[1].MI-3454(100mg/kgofPOor15mg/kgofIV)hasaT1/2of3.2hours,aCmaxof4698mg/mLforPO[1].MI-3454exhibitsfavorablestabilityinmurineandhumanlivermicrosomes(t1/2=20.4minutesand37.1minutes,respectively)[1].MI-3454demonstrateslowerlevelsinbrainandcerebrospinalfluid,suggestinglimitedabilitytocrosstheblood-brainbarrier[1].AnimalModel:8-to10-week-oldfemaleNSGmice(MV-4-11xenotransplantationmodelofMLLleukemia)[1]Dosage:120mg/kgAdministration:Orally;oneortwicedailyfor7consecutivedaysResult:Aonce-dailytreatmentwassufficienttoblockleukemiaprogression.AnimalModel:FemaleCD-1mice[1]Dosage:100mg/kg(PO)or15mg/kg(IV)(PharmacokineticAnalysis)Administration:POorIVResult:HadaT1/2of3.2hours,aCmaxof4698mg/mLforPO.HadaT1/2of2.4hours,aCLof2375mL/hours•kg,andaVssof5358mL/kgforIV.2/3MasterofSmallMolecules—您⾝边的抑制剂⼤师www.MedChemEREFERENCES[1].SzymonKlossowski,etal.MeninInhibitorMI-3454InducesRemissioninMLL1-rearrangedandNPM1-mutatedModelsofLeukemia.JClinInvest.2020Feb3;130(2):981-997.McePdfHeightCaution:Producthasno