ITRI-90-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEITRI-90Cat.No.:HY-171808CASNo.:2798907-16-9分⼦式:C₄₅H₅₆F₃N₉O₆S分⼦量:908.04作⽤靶点:AndrogenReceptor;PROTACs;Apoptosis作⽤通路:VitaminDRelated/NuclearReceptor;PROTAC;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性ITRI-90⼀种⼝服活性的雄激素受体(AR)PROTAC降解剂。ITRI-90通过泛素-蛋⽩酶体系统有效降解全长AR(AR-FL)及其剪接变异体AR-V7蛋⽩，从⽽抑制AR转录活性及其靶因表达。ITRI-90能显著抑制前列腺癌细胞的增殖(包括Enzalutamide耐药细胞)并诱导细胞凋亡(apoptosis)。ITRI-90表现出良好的药代动⼒学特性，并在体内显⽰出强⼤的抗肿瘤功效。ITRI-90可⽤于前列腺癌的相关研究[1]。体外研究ITRI-90(0-20μM,24h)reducesAR-FLandAR-V(ΔLBD)proteinsinLNCaP,CWR22Rv1,VCaPcells(withDC50=2.12,5.73and8.67nMforAR-FLproteinsandDC50=4.72and0.29nMforAR-VproteinsinCWR22Rv1,VCaPcellsrespectively)[1].ITRI-90(10μM,24h)demonstratesaprolongeddurationofeffect,enablinglessfrequentdosinginLNCaP,CWR22Rv1andVCaPcells[1].ITRI-90(10μM,6or10h)degradesARproteinlevelsviaubiquitin-proteasomedependentsysteminCWR22Rv1andITRI-126,cells[1].ITRI-90(0.1-1μM,24h)lessefficientlyinhibitsARtargetexpressiononbothARandAR-V7signalingandexertsARinhibitionmediatedviaNTD-targetedproteindegradationordirectblockadeofligandbindinginLNCaPandCWR22Rv1cells[1].ITRI-90(0.001-100μM,24hor7days)specificallyandeffectivelyinhibitscancercellproliferationandinducesapoptosisinLNCaP,CWR22Rv1andVCaPcells[1].ITRI-90(5or10μM,oneday)effectivelydegradesEnzalutamide(HY-70002)-inducedAR-FLandtruncatedARV(ΔLBD)proteinsinbothshort-termtreatedandlongtermacquiredresistantcells,therebysignificantlyimpairingtheenzalutamide-resistantcellgrowthinVCaP,C4-2BandC4-2B/EnzRcells[1].ITRI-90showslowplasmaclearancerate(6.62mL/min/kg)andachieveswellactualbodyexposure(AUC/Dose=2502.4)inmouselivermicrosomes[1].1/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEWesternBlotAnalysis[1]CellLine:LNCaP,CWR22Rv1,VCaPcellsConcentration:0,0.01,0.03,0.1,0.3,1,3,10and20μMIncubationTime:24hResult:EffectivelyreducedAR-FLandAR-V(ΔLBD)proteinsinadose-dependentmanner.WesternBlotAnalysis[1]CellLine:LNCaP,CWR22Rv1,VCaPcellsConcentration:10μMIncubationTime:24hResult:Displayeddifferentkineticsofdegradationandsustainabilityafterdrugwashoutatdifferenttime.AchievedARandAR-V(ΔLBD)degradationby24htreatment.Appearedtosustainlowproteinlevelsupto24hafterdrugwashout.WesternBlotAnalysis[1]CellLine:CWR22Rv1and293TcellsConcentration:10μMIncubationTime:6or10hResult:DegradationofARandAR-V(ΔLBD)wasrecoveredbyMG132andMLN4924treatment.ShowedARproteinsstronglyubiquitinated.CellProliferationAssay[1]CellLine:LNCaP,CWR22Rv1,VCaPcellsConcentration:0.001,0.01,0.1,1,10and100μMIncubationTime:7daysResult:Stronglyinhibitedcellgrowthbyover90%withIC50s=6.587,4.134,5.454μMforLNCaP,CWR22Rv1,VCaPcells,respectively.Activatedcaspase3/7within24h.RealTimeqPCR[1]CellLine:LNCaPandCWR22Rv1cells2/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEConcentration:0.1and1μMIncubationTime:24hResult:DecreasedKLK3,NKX3.1andTMPRSS2expressioninLNCaPandCWR22Rv1cells.ReducedCCNA2,CDC20,CDK1,UBE2C,UGT2B17andEDN2inCWR22Rv1cells.CellProliferationAssay[1]CellLine:LNCaP,CWR22Rv1,VCaPcellsConcentration:0.001,0.01,0.1,1,10and100μMIncubationTime:7daysResult:Stronglyinhibitedcellgrowthbyover90%forLNCaP,CWR22Rv1andVCaPcellswithIC50s=6.587,4.134and5.454μM.ApoptosisAnalysis[1]CellLine:LNCaP,CWR22Rv1,VCaPcellsConcentration:10μMIncubationTime:24hResult:Rapidlyactivatedcaspase3/7.WesternBlotAnalysis[1]CellLine:VCaP,C4-2B/EnzRcellscellsConcentration:10μMIncubationTime:24hResult:ReversedARdegraderssignificantlyinVCaPcell.DisplayedEnzalutamideresistanceaswellaselevatedAR-FLandAR-V7inLong-termdrugexposureofC4-2BCellsresultedinC4-2B/EnzRcells.EfficientlyreducedbothAR-FLandthetruncatedAR-Vs.CellProliferationAssay[1]CellLine:VCaP,EnzRcellsConcentration:5and10μMIncubationTime:24h3/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEResult:InhibitsVCaPproliferationwhencombinedwithEnzalutamide.SignificantlyinhibitedEnzRcellsproliferation.体内研究ITRI-90(10mg/kg,i.p.,twicedailyfor15days)significantlyimpairsthetumorgrowthwithoutobvioustoxicitiesintumorregressionoftheCWR22Rv1xenograftmicemodel[1].ITRI-90(100mg/kg,p.o.,twicedailyfor21days)isanorallyavailabledegraderspecificallytargetingAR-FLandLBD-truncatedAR-VsintumorregressionoftheCWR22Rv1xenograftmicemodel[1].AnimalModel:CWR22Rv1cells(5×106)induced-maleC.B-17SCIDmice(4-6weeks)[1]Dosage:10mg/kgAdministration:twicedailyfor15daysResult:Significantlyimpairedthetumorgrowthwithoutobvioustoxicities[1].Reachedanaveragetumorgrowthinhibition(TGI)of76.64%onday12[1].SignificantlydecreasedAR-FL12andAR-Vproteinlevelsintumorsdetectedatthefinaltimepoint[1].AnimalModel:CWR22Rv1cells(5×106)induced-maleC.B-17SCIDmice(4-6weeks)[1]Dosage:100mg/kgAdministration:p.o.,twicedailyfor21daysResult:ObservedsignificanttumorsuppressionwithanaverageTGIof71.73%withoutobvioustoxicity[1].ReducedproteinlevelsofAR-FLandARVsinthetumors[1].REFERENCES[1].HungCL,etal.TargetingandrogenreceptorandthevariantsbyanorallybioavailableProteolysisTargetingChimerascompo