BI-882370-DataSheet-生命科学试剂-MedChemExpressVIP

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEBI-882370Cat.No.:HY-107779CASNo.:1392429-79-6分⼦式:C₂₈H₃₃F₂N₇O₂S分⼦量:569.67作⽤靶点:Raf作⽤通路:MAPK/ERKPathway储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:5mg/mL(8.78mM;ultrasonicandwarmingandheatto60°C)H2O:<0.1mg/mL(insoluble)MassSolvent1mg5mg10mgConcentration制备储备液1mM1.7554mL8.7770mL17.5540mL5mM0.3511mL1.7554mL3.5108mL10mM---------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。BIOLOGICALACTIVITY⽣物活性BI-882370⼀种⾼效选择性的RAF激酶抑制剂，其结合位于BRAF激酶的DFG-out⽆活性构象处(ATP结合位点)。BI-882370抑制BRAFV600E-mutant,WTBRAF和CRAF激酶的IC50值分别为0.4，0.8和0.6nM。BI-882370也可以抑制SRC家族激酶。1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEIC50&TargetBrafc-RafBRafV600E0.6nM(IC50)0.8nM(IC50)0.4nM(IC50)体外研究BI-882370(0.9-6000nM;3days)inhibitstheBRAF-mutanthumanmelanomaandcolorectalcancercellsproliferationwithaEC50rangeof1-10nM[1].BI882370(0.1-100nM,0.1-3000nM;2hours)resultsinareductionofp-MEK1/2,p-ERK1/2andcyclinD1/D2expressioninBRAFV600E-mutantA375cells;inducesphosphorylationofMEK1/2andenhancedphosphorylationofERK1/2inWTBROcells(3-300nM)[1].BI882370(0.1-100nM,0.1-3000nM;24hours)suppressescyclinD1/D2expression,inducesKip1/p27expressionatconcentrationsof1nMorhigherinBRAFV600E-mutantA375cells,expressionofcyclinsD1/D2orKip1/p27isnotaffectedinWTBROcells[1].CellProliferationAssay[1]CellLine:BRAF-mutantandWTmelanomacelllines(A101D,A375,SK-MEL-28,G-361,andBRO);Colorectalcancercelllines(COLO205,HT-29,LS411N,andHCT-116)Concentration:0.9-6000nMIncubationTime:3daysResult:ShowedaEC50rangeof1-10nMinanextendedpanelofBRAF-mutanthumanmelanomaandcolorectalcancercell;whileproliferationofBRAFWTcellswasinhibitedwithEC50>1μM.WesternBlotAnalysis[1]CellLine:BRAFV600E-mutantA375cells;BRAFWT,NRAS-mutantBRO(WTBRO)cellsConcentration:0.1-100nM;0.1-3000nMIncubationTime:2hours;24hoursResult:Resultedinareductionofphospho-MEK1/2signalsandcyclinD1/D2expressioninBRAFV600E-mutantA375cells.体内研究BI-882370(deliverorally;25mg/kg,50mg/kg;twicedaily;2weeks)isefficaciousinmultiplemousemodelsofBRAF-mutantmelanomasandcolorectalcarcinomas,showssuperiorefficacycomparedwithVemurafenib,Dabrafenib,orTrametinib[1].BI-882370(deliverorally;25mg/kg;twicedaily;40days)developesresistancewithin3weeks,butresistanceisnotobservedduring5weeksofsecond-linetherapyincombinationwithtrametinib[1].BI-882370(deliverorally;60mg/kg;oncedaily;2weeks)indicateslackoftoxicityintermsofclinicalchemistry,hematology,pathology,andtoxicogenomicsinrats[1].AnimalModel:HumanmelanomaxenograftsinnudemicewithBRAF-mutantmelanomasandcolorectalcarcinomascells(A375,COLO205;G-361,HT-29cells)[1]Dosage:25mg/kg;50mg/kg2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAdministration:Deliverorally;25mg/kg,50mg/kg;twicedaily;2weeksResult:Regressedtumorspartially,upondiscontinuation,tumorregrowthwasmarkedlydelayed.REFERENCES[1].WaizeneggerIC,etal.ANovelRAFKinaseInhibitorwithDFG-Out-BindingMode:HighEfficacyinBRAF-MutantTumorXenograftModelsintheAbsenceofNormalTissueHyperproliferation.MolCancerTher.2016Mar;15(3):354-65.McePdfHeightCaution:Producthas