BMS-986126-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEBMS-986126Cat.No.:HY-124995CASNo.:1610017-20-3分子式:C₂₂H₂₅FN₆O₂分子量:424.47作用靶点:IRAK;Toll-likeReceptor(TLR);ERK;NF-κB;InterleukinRelated作用通路:Immunology/Inflammation;MAPK/ERKPathway;StemCell/Wnt;NF-κB储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性BMS-986126是一种强效、选择性强且口服有效的IRAK4抑制剂(IC50=5.3nM)。BMS-986126可广泛抑制MyD88依赖性信号通路。BMS-986126在MRL/lpr和NZB/NZW小鼠狼疮模型中表现出显著的活性，可抑制多种致病反应。BMS-986126可用于自身免疫性疾病的相关研究，例如系统性红斑狼疮(SLE)[1]。IC50&TargetIRAK45.3nM(IC50)体外研究BMS-986126demonstratessimilar,nanomolarpotency(IC50:135-456nM)againstmultipleMyD88-dependentTLRs(TLR2/5/7/9)inhumanPBMCs,aswellaspotentinhibitionofbothNF-κB-regulated(IL-6)andtypeIIFN(IFN-α)responses,extendingtocytokinesinducedbyIL-1βandIL-18[1].BMS-986126failstosignificantlyaffectcytokineproductioninducedbytheMyD88-independentagonistsTLR3andTNF-α[1].BMS-986126(0-2μM,30min)dose-dependentlyinhibitsthephosphorylationofIKKα/βandERKdownstreamofTLR2andTLR4,andERKdownstreamofTLR7inhumanPBMCs[1].BMS-986126demonstratesequivalentpotencyininhibitingTLR7/9-inducedinterferonresponsegeneexpression(e.g.,IFIT1)inPBMCsfrombothhealthydonorsandpatientswithSLE[1].BMS-986126(5μM,30min)broadlyreversesthegeneexpressionprofileinducedbyTLR7activationinhumanPBMCs,withasignificantproportionoftheinhibitedgenesbeingcanonicalinterferon-stimulatedgenes[1].BMS-986126(16-80nM,30min)exhibitsasynergisticeffectwithPrednisolone(HY-17463)insuppressingTLR9-inducedandfluvirus-inducedIFIT1expressioninhumanPBMCs,showingsignificantlygreater1/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEinhibitionthaneithersingleagent[1].WesternBlotAnalysis[1]CellLine:PBMCsConcentration:0,0.07,0.22,0.67,2μMIncubationTime:30minResult:InhibitedLPS-inducedIKKα/bandERKphosphorylation.InhibitedTLR2-inducedIKKα/bandERKphosphorylation.RobustlyinhibitGardiquimod(HY-103697)-inducedERKphosphorylation体内研究BMS-986126(0.1-3mg/kg,p.o.,singledose30minpre-LTA/CpG-ODN/Gardiquimod)inhibitscytokineproductiondownstreamofmultipleMyD88-dependentTLRs(TLR2/7/9)inmice[1].BMS-986126(0.3-10mg/kg,p.o.,dailyfor6daysor8weeks)significantlyinhibitsdiseaseactivityinbothspontaneous(MRL/lprandNZB/NZW)murinelupusmodels[1].AnimalModel:FemaleBALB/cmiceintraperitoneallyinjectedwithLTA(25mg/kg)[1]Dosage:0.1,0.3,1.0,and3.0mg/kgAdministration:p.o.,singledose30minpre-LTAResult:Dose-dependentlysuppressedLTA-inducedIL-6plasmalevels,withmaximalinhibitionobservedatthetopdoseof3mg/kg.AnimalModel:MaleC57BL/6mice(12-week-old)intravenouslyinjectedwithCpG-ODN(2.5μg)[1]Dosage:1and3mg/kgAdministration:p.o.,singledose30minpre-CpG-ODNResult:StronglysuppressedIFN-αatboth2and8hafterCpG-ODNchallenge.NoIFN-αwasdetectedinanygroupat24hafterCpG-ODNchallenge.AnimalModel:MaleC57BL/6mice(12-week-old)intraperitoneallyinjectedwithGardiquimod(5mg/kg)[1]Dosage:1and3mg/kgAdministration:p.o.,singledose30minpre-GardiquimodResult:Dose-dependentlysuppressedbothIFN-αandIL-6productionatboth2and8hafterGardiquimodchallenge.2/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEAnimalModel:MaleMRL/lprmice(12-14weeksold)[1]Dosage:0.3,1,3,and10mg/kgAdministration:p.o.,dailyfor8weeksResult:Dose-dependentlysuppressedbiomarkersofkidneydamageandsystemicinflammation.Showedverystronginhibitionofkidneydamageendpoints,includingreductionofabsoluteproteinlevelsintheurine,urineNGALlevels,andserumbloodureanitrogen.Demonstratedsignificantprotectionofallendpointsat1mg/kg.Dose-dependentlysuppresseddsDNA-specificautoantibodytiters,aswellasplasmalevelsofIL-10andIL-12p40.SignificantlysuppressedthepercentageofsplenicIFN-α+pDCsatboththe1and10mg/kgdoses.SuppressedIL-6productionbysplenicCD11b+myeloidcells.AllbutthelowestdoseinhibitedIgGdepositioninthekidney.Dose-dependentlysuppressedhistopathologyinthekidney.AnimalModel:MaleC57BL/6miceinducedbyImiquimod(HY-B0180)[1]Dosage:0.3,1,3,and10mg/kgAdministration:p.o.,dailyfor6daysResult:Dose-dependentlysuppressedskinthickening,scaling,erythema,andspleenweightgain.Significantlyinhibitedskinhistopathologyat3and10mg/kg.MaintaineditsplasmalevelsabovethemouseinvitrowholebloodLTA-inducedIL-6IC50valuefor24h.MaintaineditsconcentrationsabovethemousewholebloodIC50value(LTA-inducedIL-6IC50)for8-12houtoftheday.AnimalModel:FemaleNZB/NZWmice(12-14weeksold)[1]Dosage:0.3,1,3,and10mg/kgAdministration:p.o.,dailyfor25weeksResult:Stronglysuppressedbiomarkersofkidneydamageatalldosestested,includingurineproteinlevelsandurinelevelsofNGAL.Dose-dependentlysuppressedsystemicendpointsincludingdsDNA-specificautoantibodytitersandplasmaIL-12p40levels.InhibitedthepercentageofsplenicIFN-α+pDCs.3/4 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemESignificantlyinhibitedtheexpressionoftheIFNresponsegeneIFIT1inperipheralblood.Dose-dependentlyinhibitedIgGdepositioninthekidney.Significantlysuppressedhistopathologyinthekidneyswithprofoundeffectsonglomerulardamageandtubulardamagesubscores.REFERENCESShaileshDudhgaonkar,etal.SelectiveIRAK4InhibitionAttenuatesDiseaseinMurineLupusModelsandDe