KRAS-G12C-inhibitor-57-DataSheet-生命科學(xué)試劑-MCE

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEKRASG12Cinhibitor57Cat.No.:HY-151968CASNo.:2821863-70-9分?式:C??H??FN?O?分?量:607.72作?靶點(diǎn):Ras作?通路:GPCR/GProtein儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性KRASG12Cinhibitor57(Compound50)?種有效的、選擇性的、共價(jià)的和具有?服活性的KRASG12C抑制劑，在KRASG12C/SOS1結(jié)合試驗(yàn)中對(duì)KRASG12C的IC50為0.21μM。KRASG12Cinhibitor57誘導(dǎo)癌細(xì)胞凋亡(apoptosis)。IC50&TargetKRAS(G12C)0.21μM(IC50,KRASG12C/SOS1bindingassay)體外研究KRASG12Cinhibitor57(Compound50)(0-10μM;3days)hasselectiveinhibitiononKRASandKRAS-drivencelllines,togetherwithstronginhibitionondownstreamsignaling[1].KRASG12Cinhibitor57(0.1-1μM;24h)inducesH358cellapoptosis[1].KRASG12Cinhibitor57(0.1-1μM;48h)inhibitstumormetastasisinH358cells[1].WesternBlotAnalysis[1]CellLine:H358(KRASp.G12C)cellsConcentration:0,0.1,0.3,0.5,1and5μMIncubationTime:4and24hResult:InhibitedtheactiveKRAS-GTPandthephosphorylationofERKandAKT(MAPKandPI3Kpathway)inthedose-andtime-dependentmanners,andstronginhibitoryeffectsonthephosphorylationofERKattheconcentrationof0.1μM.IncreasedthecleavedPARPandcaspase-7induction(24h).1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEWesternBlotAnalysis[1]CellLine:H1975celllineConcentration:5,10,and20μMIncubationTime:4hResult:InterruptedthephosphorylationofERK.CellProliferationAssay[1]CellLine:H358cellsharboringKRASp.G12C,MIAPaca2cellsharboringKRASp.G12C,H1975cellsharboringKRASp.WTandA549cellsharboringKRASp.G12SConcentration:0-10μMIncubationTime:3daysResult:DisplayedfavourableinhibitoryactivitiesonH358cellsandMIAPaca2cellswiththeIC50valuesof0.16μMand0.87μM,insharpcontrastwithnoobviousinhibitiononcellproliferationonH1975cells(IC50=7.91μM)andA549cells(IC50=29.9μM).ApoptosisAnalysis[1]CellLine:H358celllineConcentration:0.1,0.3,0.5and1μMIncubationTime:24hResult:Inducedcellularapoptosisindose-dependentmanner.CellMigrationAssay[1]CellLine:H358cellsConcentration:0.1,0.5and1μMIncubationTime:48hResult:Significantlysuppressedthemigration.CellInvasionAssay[1]CellLine:H358cellsConcentration:0.1,0.5and1μMIncubationTime:48h2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEResult:Inhibitedthecellularinvasionandexhibitedthedose-dependentinhibitorypotency.體內(nèi)研究KRASG12Cinhibitor57(Compound50)(10and30mg/kg;p.o.;dailyfor20days)showsanti-tumorefficacyinmiceH358xenograftmodel[1].PharmacokineticdataofKRASG12Cinhibitor57(Compound50)inICRmice.[1]Parameteriv(3mg/kg)Parameterpo(30mg/kg)AUC(0?t)(h*ng/mL)801AUC(0?t)(h*ng/mL)600AUC(0?∞)

(h*ng/mL)804AUC(0?∞)(h*ng/mL)835C0(ng/mL)1964Cmax(ng/mL)316T1/2(h)0.930T1/2(h)4.79Vss(L/kg)4.98Tmax(h)0.083CL(mL/h/kg)3739F(%)10.4AUCo?inf(h*mg/mL)7060±1020(14.5%)21800±2310(10.6%)101000±16700(16.6%)AnimalModel:BALB/c-nu/numice,H358xenograftmodel[1]Dosage:10mg/kgand30mg/kgAdministration:Oraladministration,dailyfor20daysResult:Significantlyinhibitedthetumorgrowthinadose-dependentmannerwithremarkabletumorregressionatthedoseof30mg/kg(tumorgrowthinhibition,TGI=84.0%).Alldosagegroupswerewell-toleratedwithnolossofbodyweightandnomorphologicaldamagetovisceraincludingtheheart,spleen,andkidney.SignificantlysuppressedthephosphorylationofERKandAKTintumorsofnudemicewhendosingorallyat10mg/kgand30mg/kg.AnimalModel:ICRmice[1]Dosage:3mg/kgor30mg/kgAdministration:IVorPO(PharmacokineticAnalysis)Result:Displayedreasonableclearanceandhalf-lifebyivadministration.Showedamoderateoralbioavailability(F)of10.4%.REFERENCES[1].SongZ,etal.IdentificationofnovelPyrrolo[2,3-d]Pyrimidine-basedKRASG12Cinhibitorswithanticancereffects.EuropeanJournalofMedicinalChemistry,2022:114907.McePdf