PROTAC-FGFR2-degrader-1-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEPROTACFGFR2degrader1Cat.No.:HY-163985分⼦式:C₄₆H₅₄N₁₀O₇分⼦量:858.98作⽤靶点:PROTACs;FGFR;Apoptosis作⽤通路:PROTAC;ProteinTyrosineKinase/RTK;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性PROTACFGFR2degrader1(compoundN5)⼀种有效靶向FGFR2的PROTAC，DC50为6.46nM，IC50为0.08nM。PROTACFGFR2degrader1具有抗增殖活性和⾼度选择性，通过降低FGFR2下游蛋⽩p-ERK和p-PLCγ的激活，诱导KATOIII和SNU16周期阻滞于G0/G1期，抑制细胞凋亡(Apoptosis)。PROTACFGFR2degrader1在0.17nM浓度下对胃癌细胞的抑制率保持在50%以上。PROTACFGFR2degrader1有效抑制了⼩⿏模型中SNU16异种移植肿瘤的⽣长(SrtuctureNote:Pink，FGFR2激活剂：HY-18708;Blue，E3连接酶配体：HY-10984;Black，linker：HY-163989;E3连接酶配体+linker：HY-163986)[1]。IC50&TargetFGFR2体外研究PROTACFGFR2degrader1(0-1000nM,72h)IC50islessthan0.17nMforbothKatoIIIandSNU16[1].PROTACFGFR2degrader1(500nM;12h;WB)inducesFGFR2degradationinKatoIII,whichishighlyselectiveforFGFR2andUPS-dependent[1].PROTACFGFR2degrader1(500,1000nM;24h)inducescellcyclearrestofKatoIIIandSNU16cellsinG0/G1phase[1].WesternBlotAnalysis[1]CellLine:KATOIII,SNU16Concentration:0,0.1,1,10,100,500,1000nMIncubationTime:0,1,6,12,24,36hResult:DegradedFGFR2inKatoIIIcellswithtimedependent.InducedFGFR2degradationinSNU16cellsinvivoinamousemodel.DecreasedCDK2,CDK4,CyclinD1andCyclinE.1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEWesternBlotAnalysis[1]CellLine:KATOIII,SNU16Concentration:500nM,12h;Pomalidomide(10μM),Erdafitinib(10μM),MG132(5μM)for6h;50,100,500nMfor24hIncubationTime:12h;24hResult:DegradedFGFR2viatheUPSpathway,anddegradationofFGFR2wasdependentontheformationoftheFGFR2-N5-E3ligasecomplexandsubsequentproteasomaldegradation.Showedthatphosphorylationofp-AKTwasdecreasedinbothSNU16andKatoIIIcells,inhibitedtheactivationofp-ERKandp-PLCγeffectively.RealTimeqPCR[1]CellLine:KATOIIIConcentration:500nMIncubationTime:12hResult:DegradedFGFR2inKATOIIIwithhighselectivity.CellCycleAnalysis[1]CellLine:KATOIII,SNU16Concentration:500,1000nMIncubationTime:24hResult:ShowedthatthepercentageofKATOIIIcellsintheG0/G1phaseincreasedfrom47.7%to67.1%inthe1000nMofPROTACFGFR2degrader1,thenumberofSNU16cellsincreasedfrom45.9%to67.5%.ApoptosisAnalysis[1]CellLine:KATOIII,SNU16Concentration:1000nMIncubationTime:24hResult:ShowedthattheapoptosisrateofKATOIIIcellsincreasedfrom10.9%intheDMSOgroupto30.5%,upregulationofcleavedcaspase3wasobserved.体内研究PROTACFGFR2degrader1(10mg/kg,20mg/kg;Intraperitonealinjection)inhibitsgastriccancergrowthintheSNU16subcutaneousxenografttumormodelinvivo[1].2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEPharmacokineticprofilesofPROTACFGFR2degrader1inSDrats.[1]ParametersPROTACFGFR2degrader12mg/kg(i.v.)ParametersPROTACFGFR2degrader12mg/kg(i.p.)t1/2(h)4.65±4.14t1/2(h)7.59±0.365Tmax(h)/Tmax(h)0.25±0.177Cmax(ng/mL)/Cmax(ng/mL)302±33.7MRTinf(h)2.27±1.44MRTinf(h)6.53±0.0721CL(mL/min/kg)59.3±8.35CL/F(mL/min/kg)78.2±1.62Vss(L/kg)7.58±3.80VZ/F(L/kg)51.4±2.40AUC0-t(h*ng/mL)544±74.2AUC0-t(h*ng/mL)991±20.7AUC0-inf(h*ng/mL)570±83.3AUC0-inf(h*ng/mL)1066±21.9AUC0-t/AUC0-inf0.956±0.0232AUC0-t/AUC0-inf0.930±0.00429F/F(%)74.8±1.53AnimalModel:SDrats[1]Dosage:2,5mg/kgAdministration:Intravenousinjection(i.v.);Intraperitonealinjection(i.p.)Result:Absorbedrapidlyinvivo,reacheditsmaximumconcentrationat0.25hby5mg/kg,andthenslowlyclearedfromthebody,withahalf-lifeof7.59h.AnimalModel:AmousemodelofsubcutaneousxenograftofSNU16tumor[1]Dosage:10,20mg/kgAdministration:Intraperitonealinjection(i.p.);oncedaily;25daysResult:Showedthestrongeranti-tumoreffect,greatertumorgrowthinhibitionandasignificantreductionintumorweight.REFERENCES[1].ZhanzhanFeng,etal.SynthesisandidentificationofaselectiveFGFR2degraderwithpotentMc