PROTAC-MNK1-degrader-1-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEPROTACMNK1degrader-1Cat.No.:HY-176428分⼦式:C₃₅H₃₈N₆O₆S分⼦量:670.78作⽤靶点:PROTACs;MNK;Apoptosis;EukaryoticInitiationFactor(eIF)作⽤通路:PROTAC;MAPK/ERKPathway;Apoptosis;CellCycle/DNADamage储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性ROTACMNK1degrader-1⼀种选择性MNK1PROTAC降解剂，其在MV4-11细胞中的DC50为11.92nM，Dmax>96%。PROTACMNK1degrader-1显著降低p-eIF4E⽔平(IC50为22.07nM)，诱导细胞凋亡(apoptosis)，并将细胞周期阻滞于G1期。PROTACMNK1degrader-1具有强效的抗肿瘤活性。PROTACMNK1degrader-1在MV4-11异种移植⼩⿏模型中表现出强⼤的抗⽩⾎病功效，且具有可接受的药物安全性[1]。粉⾊：MNK1ligand(HY-176429)；蓝⾊：CRBNligaseligand(HY-A0003)；⿊⾊：linker(HY-Y1139)；CRBN+linker：HY-176430IC50&TargetMNK1eIF411.92nM(DC50)22.07nM(IC50)体外研究PROTACMNK1degrader-1(CompoundP11-2)(0.001-10μM,24h)significantlyenhancesanti-proliferativeactivityinfourcancercelllines,withIC50sof0.045,0.24,0.61and2.06μMforMV4-11,MM.1S,MOLM-13,andMDA-MB-231cells,respectively[1].PROTACMNK1degrader-1(300nM,1-24h)CRBN-andproteasome-dependentlyinducesMNK1degradationwithat1/2of3.64hinMV4-11cells[1].PROTACMNK1degrader-1(10-1000nM,24h)effectivelyinhibitstumorcellproliferationbyselectivelydegradingMNK1andreducesproteinlevelofp-eIF4E(downstreamfactor)withanIC50of22.07nMinMV4-11cells[1].PROTACMNK1degrader-1hassuperiorbindingcapacityonactivepocketofCRBNandMNK1,withthelinkerformingahydrogenbondwithH353[1].PROTACMNK1degrader-1(30-300nM,24h)dose-dependentlyinducescellapoptosis(especiallyinlateapoptosis)andarrestscellcycleintheG1phaseinMV4-11cells[1].WesternBlotAnalysis[1]1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellLine:MV4-11cellsConcentration:0.001,0.003,0.01,0.03,0.1,0.3,1,3μMIncubationTime:1,2,4,8,16,24hResult:Dose-dependentlyreducedtheproteinlevelsofMNK1withaDC50of11.92nMandaDmax>96%inMV4-11cells.RapidlydegradedMNK1atthedoseof300nM,withat1/2of3.64hinMV4–11cells.InducedMNK1degradationinaCRBN-andproteasome-dependentmanner,whilebortezomibsignificantlydiminishedthedegradationinMV4-11cells.SelectivelydegradedMNK1andreducedproteinlevelofp-eIF4EwithIC50of22.07nMinMV4-11cells.WesternBlotAnalysis[1]CellLine:MOLM-13,MM.1S,MDA-MB-231cellsConcentration:MOLM-13andMM.1Scells(0.01,0.03,0.1,0.3,1μM),MDA-MB-231cells(0.1,0.3,1,3,10μM)IncubationTime:24hResult:Dose-dependentlyreducedtheproteinlevelsofMNK1inMOLM-13,MM.1S,andMDA-MB-231cells,withapronounceddegradationeffectinMM.1Scells.ApoptosisAnalysis[1]CellLine:MV4-11cellsConcentration:30,100,300nMIncubationTime:24hResult:Dose-dependentlyinducedapoptosis(especiallyinlateapoptosis)withthetotalapoptoticpercentageofthecellincreasedto13.9,27.8,and70.7%inMV4-11cells.CellCycleAnalysis[1]CellLine:MV4-11cellsConcentration:30,100,300nMIncubationTime:24hResult:SignificantlyincreasedtheproportionofcellsintheG1phaseanddecreasedtheproportionsintheSandG2phasesinadose-dependentmanner.2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE体内研究PROTACMNK1degrader-1(CompoundP11-2)(20mg/kg,i.p.,dailyfor16days)significantlyinhibitstumorgrowthbythedegradationofMNK1andfurtherreducingthelevelofp-eIF4EintheMV4-11xenograftmicemodel[1].PROTACMNK1degrader-1(100mg/kg,i.p.,dailyfor14days)hasacceptabledrugsafety,withnoevidenttoxicitytowardsothermajororgans[1].AnimalModel:FemaleNSGmice(5weeksold)wereinjectedsubcutaneouslyintotherightflankwithMV4-11cells(5×106cells/mouse)toinducetumors[1].Dosage:20ꢀmg/kgAdministration:i.p.,dailyfor16ꢀdaysandthenmeasuredbodyandtumorweight1.Result:Almostcompletelyinhibitedtumorgrowthwithinhibitionrateofover90%.SignificantlyreducedtheproteinlevelofMNK1andp-eIF4E,butnosignificantchangeinMNK2intumortissues.DidnotcauseanyhepatotoxicitywithnodistinctchangeinthelevelsofALT,TBIL,ALP,andTBA,butsignificantlyreducedthelevelsofAST,UA,BUN,andCR,protectingliverandkidneyfunctionatthetherapeuticdose.AnimalModel:MaleICRmice(6weeksold)[1].Dosage:100ꢀmg/kgAdministration:i.p.,dailyfor14ꢀdaysandthencollectedbloodsamplesandotherorgans1.Result:Didnotinducesignificanthistopathologicalabnormalitiesinmajororgans(heart,liver,spleen,lungs,andkidneys),andserumbiochemicalparameters(ALT,DBIL,TBIL,ALP,TBA,BUN,CR,UA,andCK-MB)remainedwithinnormalphysiologicalranges.REFERENCES[1].YangZ,etal.DiscoveryofP11-2:APotentFirst-in-ClassMNK1-TargetingPROTACDegraderfortheTreatmentofCancer.JMedCh