Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEHBS-101Cat.No.:HY-178164分子式:C??H??F?O?分子量:346.41作用靶點:Apoptosis;Akt;mTOR;STAT;NF-κB作用通路:Apoptosis;PI3K/Akt/mTOR;JAK/STATSignaling;StemCell/Wnt;NF-κB儲存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性HBS-101是一種具有選擇性、口服活性、可穿透血腦屏障的Midkine(MDK)抑制劑(KD=38.4nmol/L)。HBS-101顯著降低細胞活力、克隆形成存活率、侵襲性，并增加細胞凋亡(apoptosis)。HBS-101涉及抑制Akt/mTOR、STAT3和NF-κB通路。HBS-101可用于三陰性乳腺癌(TNBC)的研究[1]。體外研究HBS-101(0.1-10μM,5days)significantlyreducescellviabilityofTNBCcelllines[1].HBS-101(0-5μM)reducesthecolony-formingabilityofTNBCcellsinadose-dependentmanner[1].HBS-101(20μM,24h)inducesapoptosisinTNBCcells,butnotinnormalmammaryepithelialcells[1].HBS-101(20μM,20h)significantlyreducestheexpressionofMDKreceptors,specificallyNotch2,inHCC-70cells;inhibitsdownstreamsignalingpathways,includingmTOR,STAT3,andNF-κB;andincreasescleavedcaspase-3levels[1].HBS-101(20μM,24h)downregulatesMDKtargetgenesandsignificantlyreducesSTAT3andNF-κBreporteractivityinTNBCcellsthatstablyexpressthesereporters[1].CellViabilityAssay[1]CellLine:SUM-159,BT-549,MDA-MB-468,MDA-MB-231,MDA-MB-231-BrM2-831,HCC-70,HCC-1937,HER2+SKBR3,ER+MCF7,MCF10AConcentration:0.1μM,1μM,10μMIncubationTime:5daysResult:SignificantlyinhibitedtheviabilityofTNBCcelllines,withIC50valuesrangingfrom0.3to2.8μmol/L.ExhibitedweakerinhibitoryeffectsonHER2+SKBR3,(IC50~16μM)andER+MCF7,1/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemE(IC50>20μM)breastcancercelllines.ShowednotoxicityagainstnormalbreastepithelialMCF10Acells.WesternBlotAnalysis[1]CellLine:HCC-70cellsConcentration:20μMIncubationTime:20hResult:ReducedNotch2receptorproteinlevels.InhibitedthephosphorylationofmTOR,STAT3,andNF-κB,andincreasedthelevelofcleavedcaspase-3,amarkerofapoptosis.RT-PCR[1]CellLine:MDA-MB-231cells,BT-549cellsConcentration:20μMIncubationTime:20hResult:SignificantlyreducedSTAT3andNF-κBreporteractivityinTNBCcellsthatstablyexpressthesereporters.CellInvasionAssay[1]CellLine:MDA-MB-231cells,BT-549cells,MCF10AcellsConcentration:20μMIncubationTime:24hResult:InducedapoptosisinTNBCcells,butnotinnormalmammaryepithelialcells.體內(nèi)研究HBS-101(1mg/kg(i.v.),10mg/kg(p.o.)hasrapidinvivodispositionkineticsandextremelyhighoralbioavailabilityinrats[1].HBS-101(10mg/kg,i.p.)canberapidlyabsorbedandeffectivelypenetratestheblood-brainbarrierinmice[1].HBS-101(2-10mg/kg,p.o.,5days)dosesupto10mg/kg(oral)for5consecutivedaysaresafeanddonotproduceobservableorgantoxicityinmice[1].HBS-101(2mg/kg,5mg/kg,p.o.,5days)effectivelyinhibitsthegrowthofTNBCorthotopictumorswithoraladministration,and5mg/kgisdeterminedtobetheminimumeffectivedoseinmice[1].HBS-101(5mg/kg,p.o.,5daysaweek)reducestheproliferativeactivityoftumorsinMDA-MB-231cellsxenograftmice[1].HBS-101(10mg/kg,i.p.,5daysaweek)exhibitspotentanti-tumoractivityinabrainmetastasismodelin2/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEmice[1].AnimalModel:Rats[1].Dosage:1mg/kg,10mg/kgAdministration:I.v.,p.o.Result:Hadmonoexponentialdispositioninvivoandhadanestimatedplasmahalf-lifebetween0.7and1.6hours.Hadexcellentoralbioavailabilityinrats.AnimalModel:FemaleC57BL/6mice[1].Dosage:10mg/kgAdministration:I.p.,onceResult:Absorbedrapidlyfollowingi.p.administration,resemblingani.v.bolusdrugadministration.Detectedinthebrain,withpeakdetectablelevelsreaching1,654ng/g10minutesafteradministration,suggestingthatHBS-101effectivelycrossestheblood-brainbarrier.AnimalModel:FemaleC57BL/6mice[1].Dosage:2mg/kg,5mg/kg,10mg/kgAdministration:P.o.,5daysResult:Noabnormalitiesweredetectedduringthegrosspathologicalexaminationoftheanimals.AnimalModel:MDA-MB-231cells(2×106)mixedwitha1:1volumeofMatrigelwereinjectedintothemammaryfatpadofthenudemice[1].Dosage:2mg/kg,5mg/kgAdministration:P.o.,5timesaweekResult:Ledtoasignificantdose-dependentreductionintumorvolume.Notaffectedmousebodyweight.SignificantdecreasedinKi-67–positivecells.AnimalModel:FemaleSCIDmicewereusedasrecipientsfor2mm3TNBC–PDX-96tumortissueimplantstoestablishsubcutaneousPDXtumormodels[1].Dosage:5mg/kg3/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEAdministration:P.o.,5timesaweekResult:SignificantlyinhibitedPDXtumorgrowth,withtumorvolumeandweightsignificantlyreduced.SignificantdecreaseinKi-67-positivecells.AnimalModel:1.75×105brain-metastaticMDA-MB-231-BrM2-831cellswereorthotopicallyinjectedintotherightcerebralhemisphereoffemaleNOD.CB17-Prkdcscid/NCrCrlmice[1].Dosage:10mg/kgAdministration:I.p.,5timesaweekResult:Significantlyreducedtumorprogressionandextendedthesurvivalofmicewithorthotopictumors.REFERENCESMahajanM,etal.TheDiscoveryandCharacterizationofHBS-101,aNovelInhibitorofMidkine,asaTherapeuticAgentfortheTreatmentofTriple-NegativeB