Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEDerazantinibCat.No.:HY-19981CASNo.:1234356-69-4Synonyms:ARQ-087分?式:C??H??FN?O分?量:468.57作?靶點:FGFR作?通路:ProteinTyrosineKinase/RTK儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:25mg/mL(53.35mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.1342mL10.6708mL21.3415mL5mM0.4268mL2.1342mL4.2683mL10mM0.2134mL1.0671mL2.1342mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結(jié)果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)配，當天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.5mg/mL(5.34mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.34mM);ClearsolutionBIOLOGICALACTIVITY?物活性Derazantinib(ARQ-087)?種有效的，具有?服活性的，ATP競爭型的酪氨酸激酶抑制劑；抑制軟?細胞FGFR1-3的IC50值分別為4.5，1.8和4.5nM。IC50&TargetFGFR1FGFR2FGFR34.5nM(IC50)1.8nM(IC50)4.5nM(IC50)體外研究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].體內(nèi)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?邊的抑制劑?師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