USP1-IN-15-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEUSP1-IN-15Cat.No.:HY-180216分⼦式:C₃₀H₂₄F₃N₉O₂分⼦量:599.57作⽤靶点:Deubiquitinase作⽤通路:CellCycle/DNADamage储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性USP1-IN-15⼀种⼝服有效且具有选择性的USP1抑制剂，其IC50为12.3nM。USP1-IN-15对USP1具有⾼度特异性，对所有脱靶去泛素化酶的抑制作⽤可忽略不计。USP1-IN-15可抑制细胞集落形成诱导S期阻滞，并稳定泛素化PCNA。USP1-IN-15还显⽰出协同抗增殖活性，并在体内实现了显著的肿瘤⽣长抑制。USP1-IN-15可⽤于BRCA突变型乳腺癌的研究[1]。IC50&TargetUSP112.3nM(IC50)体外研究USP1-IN-15(compound43)(14days)balancesprofileofpotentantiproliferativeactivitywithIC50=0.07μMinMDA-MB-436andgoodmetabolicstability(t1/2valueexceeding120min)[1].USP1-IN-15(1μM)hasahighspecificityforUSP1withnegligibleinhibitionagainstalloff-targetDUBs(USP5,USP7,USP8,USP9X,USP14,USP15,USP25,USP28,BAP1,andOTUD1)[1].USP1-IN-15(0-1000nM,0-168h)dose-andtime-dependentlypotentlyandpersistentlyinhibitsthedeubiquitinationofproliferatingcellnuclearantigen(PCNA)andinducesproteinlevelofp-H2AXinMDA-MB-436breastcancercells[1].USP1-IN-15(100-1000nM,48hor2-3weeks)inducesS-phasearrestinMDA-MB-436breastcancercells[1].USP1-IN-15(0.1-10μM,7daysor2-3weeks)dosedependentlyenhancesgrowthinhibitioncomparedtomonotherapywhencombinedwithOlaparib(HY-10162)inMDA-MB-436cells[1].USP1-IN-15(1μM,48h)hassuperiorsynergisticactivitywhencombinedwithOlaparibthroughenhancedinductionofDNAdamageandcellcyclearrestinMDA-MB-436cells[1].WesternBlotAnalysis[1]1/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellLine:MDA-MB-436cellsConcentration:0.3,1,3,10,30,100,300and1000nMIncubationTime:0,6,24,48,72,96,120,144,and168hResult:Exhibiteddeubiquitinationinhibition,increasedtheproteinlevelofubiquitinatedPCNA(ubPCNA)andinducedtheproteinlevelofp-H2AX0at48handbeyondinrangeof0-168hand300nM.IncreasedtheproteinlevelofubPCNAinadose-dependentmanneratlowerconcentrations(100and300nM).ShowedsignificantlyhigherubPCNAlevelsat100,300,and1000nM.Elevatedp-H2AXproteinlevelsat100,300,and1000nM.Immunofluorescence[1]CellLine:MDA-MB-436cellsConcentration:300nMIncubationTime:72hResult:Inducedthesuperiorp-H2AXsignalintensityandmorenuclearfoci.CellProliferationAssay[1]CellLine:MDA-MB-436cellsConcentration:100,300,1000nMIncubationTime:2-3weeksResult:Inhibitthegrowthofclonesinadose-dependentmanner.Demonstratedsuperiorantiproliferativeactivity,reducingcolonycountsby55.99%(300nM)and66.89%(1000nM).CellCycleAnalysis[1]CellLine:MDA-MB-436cellsConcentration:100,300,1000nMIncubationTime:48hResult:InducedS-phasearrestataconcentrationrangeof100-1000nM.CellViabilityAssay[1]2/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellLine:MDA-MB-436cellsConcentration:0.1,1,10μMIncubationTime:7daysResult:RevealedstrongercellgrowthinhibitionincombinationregimenswhencombinationwithOlaparib.CellCycleAnalysis[1]CellLine:MDA-MB-436cellsConcentration:1μMIncubationTime:48hResult:InducedsignificantcellcyclearrestwithmarkedaccumulationofcellsintheSphasebutinducedsignificantaccumulationofMDA-MB-436cellsatSandG2/MphaseswhencombinedwithOlaparib.Exhibitedpronouncedsynergisticeffects,resultinginamorerobustcellcycleperturbationwhencombinedwithOlaparib.WesternBlotAnalysis[1]CellLine:MDA-MB-436cellsConcentration:1μMIncubationTime:48hResult:Elevatedp-H2AXlevelswithorwithoutcombinationwithOlaparibbuthadabettereffectwhencombinatedwithOlaparib.体内研究USP1-IN-15(compound43)(40mg/kg,p.o.,oncedaily,for45days)exhibitssignificantsingle-agentantitumoractivity,producesasynergisticenhancementeffectwithOlaparibandindicatesminimalsystemictoxicityinaxenografttumormicemodel[1].AnimalModel:MDA-MB-436cells(5×106)induced-femalenudemice(6-9weeks,17-19g)[1]Dosage:40mg/kgAdministration:p.o.,oncedaily,for45days,withorwithoutcombinationwithOlaparib(30mg/kg)Result:Exhibitedthemostpotentantitumoractivity.Exhibitingthemostsignificantreduction(TGI=82.734%)intumorweight.Observednosignificantdifferencesinbodyweight.3/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEDemonstratednostatisticallysignificantdifferencesinorganindicesofheart,liver,lung,andkidney.ResultedsignificantreductionsinKi67-positivecellsinbothmonotherapyorcombinationgroups.ElevatedlevelsofubPCNAinmonotherapy.Exhibitedthehighestlevelofp-H2AX,consistentwithitsrobustDNAdamage-inducingcapability.REFERENCES[1].XiongT,etal,.DiscoveryandOptimizationofNovelTricyclicUbiquitin-SpecificProtease1InhibitorsfortheTreatmentofBRCA-MutatedBreastCancer.JM