PROTAC-HDAC6-degrader-7-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEPROTACHDAC6degrader7Cat.No.:HY-179421分⼦式:C₄₉H₅₄N₈O₆分⼦量:851作⽤靶点:PROTACs;NF-κB;NOD-likeReceptor(NLR);InterleukinRelated;TNFReceptor;HDAC作⽤通路:PROTAC;NF-κB;Immunology/Inflammation;Apoptosis;CellCycle/DNADamage;Epigenetics储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性PROTACHDAC6degrader7⼀种具有⼝服活性的，⾼效且选择性的PROTAC降解剂，靶向组蛋⽩去⼄酰化酶6(HDAC6)(IC50=118nM)。PROTACHDAC6degrader7可同时破坏HDAC6的催化结构域和锌指泛素结合结构域。PROTACHDAC6degrader7可抑制NLRP3炎症⼩体的组装和激活，并阻断NF-κB信号通路，从⽽减少关键炎症因⼦的转录和释放。PROTACHDAC6degrader7可降低NLRP3、pro-IL-1β、TNF-α和IL-6的mRNA⽔平。PROTACHDAC6degrader7可⽤于炎症性肠病(IBD)的研究[1]。IC50&TargetNF-κBIL-6NLRP3HDAC6118nM(IC50)体外研究PROTACHDAC6degrader7(Compound22f)(0-2μM,12h)exhibitspotentHDAC6degradationactivityinMV4-11cellsinaconcentration-dependentmanner(DC50=13.4nM)[1].PROTACHDAC6degrader7(25-200nM,12h)showsonlyslightdegradationofIKZF1at200nM,butnodegradationofGSPT1inMV4-11cells[1].PROTACHDAC6degrader7(0-2μM)demonstrateshighspecificitytowardHDAC6(IC50of118nM)andexhibitsnoappreciableinhibitionagainstotherHDACisotypesat10μM[1].PROTACHDAC6degrader7(0.5μM,0-24h)inducesHDAC6degradationinMV4-11cells,whichwasinitiatedwithin3hoursandreachedequilibriumwithin12hours,andthisdegradationcouldberescuedbyCRBNligandsandproteasomeinhibitors,indicatingthatthemechanismofactionistheinductionofHDAC6degradationviatheCRBN-mediatedubiquitin-proteasomepathway[1].PROTACHDAC6degrader7(0-6μM,0-24h)degradesHDAC6inJ774A.1cellsinatime-dependentmanner,withaconcentration-dependentDC50of9.20nM[1].PROTACHDAC6degrader7(1.4-1000nM,8h)significantlyinhibitsIL-1βinLPS/ATP-stimulatedJ774A.1cellsinaconcentration-dependentmanner[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEPROTACHDAC6degrader7(40-200nM,8h)significantlyreducesthelevelsofmatureIL-1βandp20inJ774A.1cellsatlowconcentrations,anddownregulatestheexpressionofintracellularNLRP3andpro-IL-1βproteinsathighconcentrations[1].PROTACHDAC6degrader7(0.2-1μM)dose-dependentlyreducesthemRNAlevelsofNLRP3,pro-IL-1β,TNF-α,andIL-6inLipopolysaccharides(HY-D1056)(LPS)-inducedJ774A.1cells[1].WesternBlotAnalysis[1]CellLine:MV4-11cellsConcentration:25nM,50nM,100nM,200nMIncubationTime:12hResult:OnlyIKZF1wasslightlydegradedat200nM,butGSPT1wasnotdegraded.ELISAAssay[1]CellLine:J774A.1cellswerepretreated3hfollowedbya4.5hpretreatmentwithLPS(1μg/mL).Afterward,thecellswerestimulatedwithATP(5mM)for30minConcentration:1.4nM,4.1nM,12.3nM,37nM,111nM,333nM,1000nMIncubationTime:8hResult:SignificantlyinhibitedIL-1βinLPS/ATP-stimulatedJ774A.1cellsinaconcentration-dependentmanner.体内研究PROTACHDAC6degrader7(Compound22f)(2-10mg/kg,p.o.,oncedailyfor9days)caneffectivelyalleviateDextransulfatesodiumsalt(MW5000)(HY-116282)(DSS)-inducedacutecolitisinmiceandimprovecoresymptoms(weightloss,diarrhea,bloodystool)andpathologicaldamage(colonshortening,tissueinflammatoryinfiltration)[1].AnimalModel:MaleC57BL/6Jmice(6-8weeksold)weregivenanaqueoussolutioncontaining2.5%(w/v)dextransulfatesodium(DSS)for9days[1].Dosage:2mg/kg,10mg/kgAdministration:P.o.,oncedailyfor9daysResult:Therateofweightlosswasreduced.DiseaseActivityIndex(DAI)scoresweresignificantlylowered.Thecolonlengthinmicewassignificantlyrestored,approachingnormallevels.Mutualepithelialregenerationwaspromoted,inflammatorycellinfiltrationwasreduced,andhistopathologicalscoresweresignificantlylowered.TheleveloftheinflammatorycytokineIL-1βwassignificantlylowerthanintheDSSmodelgroup,whilethelevelofacetylatedtubulin(Ac-tubulin),aspecificsubstrateof2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEHDAC6,wassignificantlyupregulated.REFERENCES[1].SunS,etal.Design,Synthesis,andAnti-inflammatoryActivityEvaluationforHydrazide-BasedHDAC6TargetedProteinDegraders.JMedChem.2025Nov27;68(22):24519