Axl-IN-21-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEAxl-IN-21Cat.No.:HY-179535CASNo.:1958081-87-2分⼦式:C₃₀H₂₇FN₄O₅分⼦量:542.56作⽤靶点:TAMReceptor;DiscoidinDomainReceptor;TGF-βReceptor;Hedgehog作⽤通路:ProteinTyrosineKinase/RTK;TGF-beta/Smad;StemCell/Wnt储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性Axl-IN-21⼀种⼝服有效的选择性AXL抑制剂，Kd为2.7nM，IC50为4.0nM。Axl-IN-21在保持激酶选择性的同时，对多种癌症相关激酶亦表现出较强抑制活性，包括Mer(Kd=1.4nM)、DDR1(IC50=22.2nM)、HIPK4(Kd=11.0nM)和LOK(Kd=10nM)。Axl-IN-21可通过阻断肿瘤相关成纤维细胞来的GAS6所诱导的AXL/STAT3/ABCG1信号通路，克服肿瘤微环境驱动的耐药性，从⽽恢复化疗敏感性并抑制药物外排。Axl-IN-21在MDA-MB-231细胞中能够抑制TGF-β1诱导的上⽪-间质转化、细胞迁移与侵袭。Axl-IN-21对⾮癌细胞未表现出显著毒性。Axl-IN-21可⽤于三性乳腺癌和胃癌的相关研究[1][2]。IC50&TargetDDR1MerAxlAxl22.2nM(IC50)1.4nM(Kd)4nM(IC50)2.7nM(Kd)体外研究Axl-IN-21(compound9im)(0.1-0.5μM)dose-dependentlyinhibitsAXLphosphorylationandreversestheepithelial-mesenchymaltransition(restoringEcadherinandreducingNcadherinexpression)inSNU668andMKN1gastriccancercells,evenwhencoculturedwithcancer-associatedfibroblasts(CAF),restoreschemosensitivitybyblockingCAFinducedAXLactivationanddownstreamsignaling,althoughcoculturewithCAFsnormallyreducesapoptoticmarkers(cleavedPARPandcleavedcaspase3)followingchemotherapyincluding5-Fluorouracil(5FU)(HY-90006)andcisplatin(HY-17394)[1].Axl-IN-21(0.5-32μM)exhibitslowercytotoxicityinnon-cancerouscellscomparedtoBGB324(HY-15150)[1].Axl-IN-21(0.1-0.5μM)inhibitsJAK1/STAT3,PI3K/AKTandMEK/ERKsignallingpathwaysandreducestheCAF)-inducedenhancementofcellmigrationinSNU668cellsco-culturedwithCAFs,eveninthepresenceofCAF-conditionedmediaordirectco-culture.[1].Axl-IN-21(0.5-2μM)suppressesCAF-inducedAXLactivation,downstreamsignalling,GCcellmigrationand1/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEchemoresistanceininhibitingAXLphosphorylationinSNU668coculturedwithCAFsand/ortreatedwithchemotherapeuticagents[1].Axl-IN-21(0.1-0.5μM)suppressesboththeupregulationofABCG1expressionandthephosphorylationofAXL,JAK1/STAT3,PI3K/AKT,andMEK/ERKinAXL-activatedGCSNU668cellstreatedwithrecombinantGAS6[1].Axl-IN-21decreasedABCG1expressionandincreasedcleavedcaspase-3positivecells,indicatingenhancedapoptosiswhencombinatewithCAFsand5-FU[1].Axl-IN-21(0.03-3μM,6h)hasstrongAxlkinaseinhibitioninMDA-MB-231breastcancercells[2].Axl-IN-21(0.04-5μM,96-144h)dose-dependentlyinhibitsTGF-β1-inducedAxlactivationinMDA-MB-231breastcancercells[2].Axl-IN-21(0.04-5μM,24h)inhibitsthemigratingprocessandinvasivenessinMDA-MB-231cells[2].WesternBlotAnalysis[2]CellLine:MDA-MB-231Concentration:0.03,0.1,0.3,1and3μMIncubationTime:6hResult:InhibitedphosphorylationofAxlanddownstreamsignaling(pAkt,pAxl).Immunofluorescence[2]CellLine:MDA-MB-231Concentration:0.04,0.2,1and5μMIncubationTime:96to144hResult:Dose-dependentlyrestoredtheproteinlevelsofEcadherinandN-cadherinbacktothecontrollevels.ReversedTGFβ1-inducedexpressionlevelchangesofE-cadherin(anepithelialmarker)andN-cadherin(ameschenchymalmarker)EMTmarkersinMDA-MB-231cells.CellMigrationAssay[2]CellLine:MDA-MB-231Concentration:0.2,1.0,5.0μMIncubationTime:24hResult:ModeratelyinhibitedthemigratingprocessinMDA-MB-231cells,suppressingtheTGFβ1(10ng/mL)-inducedwoundclosureby-24.2%,-50.6%,and-58.4%atconcentrationsof0.2,1.0,and5.0μM.CellInvasionAssay[2]2/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellLine:MDA-MB-231Concentration:0.04,0.2,1.0,or5.0μMIncubationTime:24hResult:Inhibitedcancercellinvasionby48.5%,52.1%,73.5%,and78.1%atconcentrationof0.04,0.2,1.0,and5.0μM,respectively.体内研究Axl-IN-21(compound9im)(90mg/kg,p.o.,dailyfor3weeks)increasesE-cadherinexpressioninCAF-mixedSNU668xenografttumors,indicatingthatitinhibitsCAF-inducedAXLactivationanddownstreamsignalingpathways[1].Axl-IN-21(30,90mg/kg,p.o.,dailyfor21days)inxenograftmodelofhighlymetastatic4T1murinebreastcancercells[2].AnimalModel:SNU668cells(1×10⁶)withorwithoutinducedCFAs(1×10⁶,allcellsin100μLPBSwith50%Matrigel)-BALB/cnudemice(5weeksold)[1]Dosage:90mg/kgAdministration:p.o.,dailyfor3weeksResult:IncreasedE-cadherinexpression.Significantlyreducedtumorvolumeandweightwhencombinedwith5-FUwhereaseitheragentalonehadonlylimitedeffects.AnimalModel:SNU668cells(1×10⁶)withorwithoutinducedCFAs(1×10⁶,allcellsin100μLPBSwith50%Matrigel)-BALB/cnudemice(5weeksold)[1]Dosage:90mg/kgAdministration:p.o.,dailyfor3weeksResult:IncreasesE-cadherinexpression.Significantlyreducedtumorvolumeandweightwhencombinedwith5-FUwhereaseitheragentalonehadonlylimitedeffects.AnimalModel:4T1cells(0.5×106)induced-femaleBALB/cmice[2]Dosage:30or90mg/kgAdministration:p.o.,dailyfor21daysResult:Didnotshowanobviouseffectongrowthoftheprimarytumor.Dose-dependentlysuppressedbothsizeandnumberoflivermetastases(21.3and13.03/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEinthe30and90mg/kgdosinggroups,respectively).REFERENCES[1].KimTH,etal.Cancer-associatedfibroblast-derivedGAS6increasesresistancetochemotherapythroughAXL/STAT3/ABCG1ingastriccancer.BrJCancer.2025Oct28.doi:10.1038/s41416-025-03218-[2].TanL,etal.4-Oxo-1,4-dihydroquinoline-3-carboxamideDer