Derazantinib-ARQ-087-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEDerazantinibCat.No.:HY-19981CASNo.:1234356-69-4Synonyms:ARQ-087分⼦式:C₂₉H₂₉FN₄O分⼦量:468.57作⽤靶点:FGFR作⽤通路:ProteinTyrosineKinase/RTK储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:25mg/mL(53.35mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.1342mL10.6708mL21.3415mL5mM0.4268mL2.1342mL4.2683mL10mM0.2134mL1.0671mL2.1342mL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；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.5mg/mL(5.34mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.34mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Derazantinib(ARQ-087)⼀种有效的，具有⼝服活性的，ATP竞争型的酪氨酸激酶抑制剂；抑制软⾻细胞FGFR1-3的IC50值分别为4.5，1.8和4.5nM。IC50&TargetFGFR1FGFR2FGFR34.5nM(IC50)1.8nM(IC50)4.5nM(IC50)体外研究Incells,inhibitionofFGFR2auto-phosphorylationandotherproteinsdownstreamintheFGFRpathway(FRS2α,AKT,ERK)isevidentbytheresponsetoDerazantinibtreatment.CellproliferationstudiesdemonstrateDerazantinibhasanti-proliferativeactivityincelllinesdrivenbyFGFRdysregulation,includingamplifications,fusions,andmutations.CellcyclestudiesincelllineswithhighlevelsofFGFR2proteinshowapositiverelationshipbetweenDerazantinibinducedG1cellcyclearrestandsubsequentinductionofapoptosis[1].DerazantinibrescuestheFGF2-mediatedgrowtharrestwithEC50atabout100nM,withnosignificanttoxicitydetectedforupto500nM.TheconcentrationrangeatwhichDerazantinibsignificantlysuppressestheFGF2effectisbetween70-500nM.DerazantinibinhibitsFGF-mediatedlossofextracellularmatrixandinductionofchondrocyteprematuresenescence.DerazantinibrescuesFGF-mediatedinhibitionofchondrocytedifferentiationintibiacultures.DerazantinibinhibitsFGFR1-4butnootherreceptortyrosinekinasesincell-freekinaseassay.DerazantinibinhibitsFGFR1andFGFR2mutantsassociatedwithcraniosynostoses.DerazantinibrescuesFGFR-mediatedbonedifferentiationinmouselimbbudmicromassculturesandexvivomousecalvarialorgancultures[2].体内研究DerazantinibiseffectiveatinhibitingtumorgrowthinFGFR2altered,SNU-16andNCI-H716,xenografttumormodelswithgeneamplificationsandfusions[1].Mostoftheembryosexhibitabnormalexternalphenotype(81.3%)inDerazantinib-injectedwings,possiblyduetoinhibitionofproliferationoflimbbudmesenchyme.Thewingsareshorterandthinner,withskeletalphenotypetypicalforFGFRinhibition,whereulnaandradiusareshorterorsmallerinsize,oroccasionallymissingcompletely[2].PROTOCOLKinaseAssay[1]DerazantinibistitratedinDMSOutilizinga3-folddilutionscheme,andthendiluted10-foldfurtherindeionizedwaterforafinalDMSOconcentrationof10%.Avolume(2.5μL)ofthesedilutionsorvehicleisaddedtoeachwellofareactionplate.FGFR1orFGFR2isaddedtoassaybuffertoeachwellinavolumeof17.5μLforafinalconcentrationof0.50or0.25nM,respectively.Aftera30-minutepre-incubationperiod,ATPandsubstrateareaddedinassaybuffer(5μL)forfinalconcentrationsof0-1,000μMATPand80nMbiotinylated-PYK2,forafinalreactionvolumeof25μL.Theplatesareincubatedfor60minutesatroomtemperature,andthenstoppedinthedarkbytheadditionof10μLstop/detectionmixturepreparedinassaybuffercontainingEDTA[1].2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEMCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.CellAssay[1]Cellsareseededat3000-5000cellsperwellwith130μLmediain96-welltissueculturetreatedplates.Thecellsareincubatedovernightandsubsequentlytreatedwith3-foldserialdilutionsofDerazantinibstartingat100μM.Thecellsarereturnedtoa37°Chumidifiedincubatorfor72hours.CellproliferationismeasuredusingMTSassay[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice:FemaleNCrnu/numice(SNU-16)orCB17SCIDmice(NCI-H716)withwellestablished(400mg)Administration[1]subcutaneoustumorsaregivenasingleoraldoseofDerazantiniborvehiclecontrol.Plasmaandtumorsamplesarecollected4hourspostsingledose.Derazantinibisadministeredorally.Dosingvolumeforallgroupsis10mL/kgor0.1mL/10gbodyweight[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].HallTG,etal.PreclinicalActivityofARQ-087,aNovelInhibitorTargetingFGFRDysregulation.PLoSOne.2016Sep14;11(9):e0162594.[2].BalekL,etal.ARQ-087inhibitsFGFRsignalingandrescuesaberrantcellproliferationanddifferentiationinexperimentalmodelsofcraniosynostosesandchondrodysplasiascausedbyactivatingmuta