Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEMI-3454Cat.No.:HY-136360CASNo.:2134169-43-8分?式:C??H??F?N?OS分?量:636.73作?靶點(diǎn):EpigeneticReaderDomain作?通路:Epigenetics儲(chǔ)存?式:4°C,storedundernitrogen*Insolvent:-80°C,6months;-20°C,1month(storedunder

nitrogen)溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:31.25mg/mL(49.08mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM1.5705mL7.8526mL15.7052mL5mM0.3141mL1.5705mL3.1410mL10mM0.1571mL0.7853mL1.5705mL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(chǔ)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(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month(storedundernitrogen)。-80°C儲(chǔ)存時(shí)，請?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)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：20%HP-β-CD>>5%CremophorELSolubility:5mg/mL(7.85mM);Suspendedsolution;Needultrasonic1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEBIOLOGICALACTIVITY?物活性MI-3454?種具有?服活性，?效和選擇性的Menin-MLL1相互作?抑制劑，IC50為0.51nM。MI-3454通過下調(diào)涉及??病發(fā)?的關(guān)鍵因，在MLL1重排或NPM1突變的??病??模型中抑制細(xì)胞增殖，誘導(dǎo)分化并完全緩解或消退??病。IC50&TargetIC50:0.51nM(menin-MLL1interaction)[1]體外研究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:7daysResult:Demonstratedstrongreductionofcellproliferation.RT-PCR[1]CellLine:HumanleukemiccelllinesMV-4-11cellsorMOLM13Concentration:50nMIncubationTime:6daysResult:LedtodownregulatedexpressionofHOXA9andMEIS1andexpressionlevelofotherMLLfusiontargetgenes,includingMEF2C,DLX2,HOXA10,PBX3,andFLT3.體內(nèi)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].2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEMI-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.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?iScience.2021Dec25;25(1):103679.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].SzymonKlossowski,etal.MeninInhibitorMI-3454InducesRemissioninMLL1-rearrangedandNPM1-mutatedModelsofLeukemia.JClinInvest.2020Feb3;130(2):981-997.