DI-1548-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEDI-1548Cat.No.:HY-156240CASNo.:2247060-97-3分⼦式:C₃₂H₄₇N₅O₄S分⼦量:597.81作⽤靶点:E1/E2/E3Enzyme;Keap1-Nrf2作⽤通路:MetabolicEnzyme/Protease;NF-κB储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性DI-1548⼀种强效、选择性、不可逆的DCN1共价抑制剂(IC50=4.6nM)。DI-1548能在纳尔浓度下强效且选择性地抑制Cullin3的neddylation修饰，对其它Cullin蛋⽩(包括Cullin1、2、4A、4B和5)的neddylation过程⽆明显响，且⽆细胞毒性。DI-1548与DCN1的共价结合会破坏DCN1-UBC12相互作⽤，导致neddylation复合物崩解，进⽽使CRL3失活，最终导致NRF2积累及其靶因的上调，从⽽在⼩⿏模型中起到保护肝脏的作⽤。DI-1548可⽤于肝损伤相关研究[1]。体外研究DI-1548(1-1000nM,24h)inhibitscullin3neddylationatconcentrationsaslowas1nMandareapproximately1000timesmorepotentthanDI-591(HY-124602)inU2OScells[1].DI-1548(0.3-1000nM,24h)inhibitstheneddylationofcullin3withover1000-foldselectivityoverothercullinmembersinvariouscelllines,includingU2OS,MDA-MB-231,KYSE70,andHCT116[1].DI-1548(0-1000nM,72h)showsnocytotoxicityinU2OS,MDA-MB-231,HCT116andKYSE70cellsatconcentrationsupto1000nM[1].DI-1548(30nM,0-48h)hasfastkineticsinselectiveinhibitionoftheneddylationofcullin3overcullin1[1].DI-1548(0.3-1000nM,1h)selectivelyandpotentlystabilizescellularDCN1inadose-dependentmanneratnanomolarconcentrations,withnoobservableeffectonDCN3[1].WesternBlotAnalysis[1]CellLine:U2OScellsConcentration:1,10,100and1000nMIncubationTime:24h1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:ReducedN-Cul3levelsat1nMandwasapproximately1000timesmorepotentthanDI-591.WesternBlotAnalysis[1]CellLine:U2OS,MDA-MB-231,HCT116andKYSE70cellsConcentration:0.3,1,3,10,30,100,and1000nMIncubationTime:24hResult:SignificantlyreducedthelevelofN-CUL3atconcentrationsaslowas0.3nM,andachievedprofoundinhibitionoftheneddylationofcullin3at1-3nM.Demonstrateover300-foldgreaterpotencythanDI-591acrossvariouscelllines.Hadnoobviouseffectontheneddylationofothercullinmembersthatwereexamined,includingcullin1,2,4A,4B,and5atconcentrationsupto1000nM.InducedsignificantaccumulationofNRF2proteinatconcentrationsaslowas0.3-1nM,andwas100-1000timesmorepotentthanDI-591.HadnoobviouseffectonproteinlevelsofKEAP1andp62inU2OScells.Hadnoeffectonthelevelsofp21andBIMproteins,substratesofCRL1,andCDT1,asubstrateofCRL4A,atconcentrationsupto1000nM,consistentwithitsinabilitytoinhibitneddylationofthesecullinmembers.CellViabilityAssay[1]CellLine:U2OS,MDA-MB-231,HCT116andKYSE70cellsConcentration:0-1000nMIncubationTime:72hResult:Showednocytotoxicityinfourcancercelllinesatconcentrationsupto1000nM.WesternBlotAnalysis[1]CellLine:U2OScellsConcentration:30nMIncubationTime:5and30min,6,24,and48hResult:Inhibitedtheneddylationofcullin3within5minbuthadnoeffectontheneddylationofcullin1withtreatmenttimeupto48h.WesternBlotAnalysis[1]CellLine:U2OScells2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEConcentration:0.3,1,3,10,30,100,and1000nMIncubationTime:1hResult:EnhancedthethermalstabilityofDCN1proteininadose-dependentmanneratconcentrationsaslowas0.3nM.Exhibitedover1000-foldgreaterpotencythanDI-591inenhancingthethermalstabilityofcellularDCN1protein.ShowednodiscernibleeffectonthethermalstabilityofcellularDCN3proteinatconcentrationsupto1000nM.体内研究DI-1548(25mg/kg,i.p.,once)elevateshepaticNRF2proteinlevelsinC57BL/6WTmice[1].AnimalModel:MaleC57BL/6WTmice(~8weeks)[1]Dosage:25mg/kgAdministration:i.p.,onceResult:InducedrobustupregulationofNRF2proteininthemouseliver.ProducedasustainedPDeffectintheliverdespitebeingclearedfromsystemiccirculationwithin3hours.REFERENCES[1].ZhouH,etal.Selectiveinhibitionofcullin3neddylationthroughcovalenttargetingDCN1protectsmicefromacetaminophen-inducedlivertoxicity.NatCommun.2021May11;12(1):2621.Mc