ONO-7475-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•Agonists•ScreeningLibrarieswww.MedChemEONO-7475Cat.No.:HY-114358CASNo.:1646839-59-9分⼦式:C₃₂H₂₆N₄O₆分⼦量:562.57作⽤靶点:TAMReceptor;TrkReceptor作⽤通路:ProteinTyrosineKinase/RTK;NeuronalSignaling储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:250mg/mL(444.39mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.7776mL8.8878mL17.7756mL5mM0.3555mL1.7776mL3.5551mL10mM0.1778mL0.8888mL1.7776mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存⽅式和期限。BIOLOGICALACTIVITY⽣物活性ONO-7475⼀种有效的、选择性的、具有⼝服活性的新型Axl/Mer抑制剂，IC50值分别为0.7nM和1.0nM。ONO-7475使AXL过表达的EGFR突变型NSCLC细胞对EGFR-TKIs敏感，抑制耐药细胞的产⽣和耐药性的维持。ONO-7475联合Osimertinib(HY-15772)为EGFR突变⾮⼩细胞肺癌(NSCLC)的研究提供了⼀个光明的前景。IC50&TargetIC50:0.7nM(AXL)[1]IC50:1.0nM(MERtyrosinekinase)[2]1/3MasterofSmallMolecules—您⾝边的抑制剂⼤师www.MedChemE体外研究ONO-7475isagainstrecombinanthumanAXLwithIC50valuesof0.414nMand0.7nMinoff-chipMSAandACDcell-basedtyrosinekinaseassay,respectively.ItisagainstAXL,MER,TYRO3,TRKB,PDGFRalpha,TRKA,andFLT3activitieswithIC50valuesof0.7nM,1.0nM,8.7nM,15.8nM,28.9nM,35.7nMand147nM,respectivelyinaCell-basedTyrosineKinaseassay[2].ONO-7475(0.0001μM-1μM;72hours)increasesthesensitivitytoOsimertinibandDacomitinibandreducestheviabilityofhighAXL-expressingPC-9andHCC4011cells,butnotoflow-AXL-expressingHCC827cells.Besides,ONO-7475enhancesOsimertinibefficacyontheviabilityofcelllinesPC-9,PC-9KGR,andHCC4011,andH1975,allofwhichexpresshighlevelsofAXL.ButithasamarginaleffectontheviabilityofcelllinesHCC827,HCC4006,andH3255withlowlevelsofAXL[1].ONO-7475(1μM;4or48hours)combineswithOsimertinibmarkedlyinhibitsthephosphorylationofAXL,AKT,andp70S6Kcomparedwiththetreatmentofthehigh-AXL-expressingcelllinestreatedwithOsimertinibaloneat4hours.ItcombineswithosimertinibincreasescleavedPARPinPC-9andHCC4011cellscomparedwiththetreatmentwithOsimertinibalone[1].CellViabilityAssay[1]CellLine:HighAXL-expressingcell:PC-9,HCC4011,H1975,PC-9KGRcellsLowAXL-expressingcell:HCC827,HCC4006,andH3255cellsConcentration:0.0001μM;0.001μM;0.01μM;0.1μM;1μMIncubationTime:72hoursResult:IncreasedthesensitivityandefficacytoOsimertinibinAXL-highlevelcells.WesternBlotAnalysis[1]CellLine:PC-9,HCC4011cellsConcentration:1μMIncubationTime:4or48hoursResult:Increasedp-AXL,AKT,andp70S6Kexpressionat4hoursandincreasesp-PARPexpressionat48hourswhencombindeswithOsimertinib.体内研究ONO-7475(oralgavage;10mg/kgorcombineswith5mg/kgOsimertinib;29days)treatmentalonehaslittleeffectonthetumorgrowth.Besides,Osimertinibalonecausestumorregressionwithinoneweek,butthetumorsreappearwithinthreeweeks.Thecombinedinitialtreatmentcausestumorregressionandthesizeoftumorsismaintainedfor4weeks.Noapparentadverseevents,includingweightlossareobservedduringthesetreatments[1].AnimalModel:MouseCDXmodelusinghigh-AXL-expressingPC-9KGRcells(exon19deletionandtheexon21-T790MmutationinEGFR)[1]Dosage:10mg/kg;oncedaily;19daysAdministration:oralgavage2/3MasterofSmallMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:Hadlittleeffectsalone,butcombinedtreatmentssignificantlydecreasedtumorvolumewithoutreappear.REFERENCES[1].OkuraN,etal.ONO-7475,aNovelAXLInhibitor,SuppressestheAdaptiveResistancetoInitialEGFR-TKITreatmentinEGFR-MutatedNon-SmallLungCancer.ClinCancerRes.2020Jan17.[2].RuvoloPP,etal.Anexelekto/MERtyrosinekinaseinhibitorONO-7475arrestsgrowthandkillsFMS-liketyrosinekinase3-internaltandemduplicationmutantacutemyeloidleukemiacellsbydiversemechanisms.Haematologica.2017Dec;102(12):2048-2057.McePdfHeig