RSC-1255-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemERSC-1255Cat.No.:HY-176954CASNo.:2171015-78-2分⼦式:C₂₇H₂₅ClF₄N₄O₃分⼦量:564.96作⽤靶点:ProtonPump;Ras;Autophagy;Apoptosis作⽤通路:MembraneTransporter/IonChannel;GPCR/GProtein;MAPK/ERKPathway;Autophagy;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性RSC-1255⼀种⾼效且选择性的V-ATPase抑制剂，可直接结合哺乳动物V-ATPase复合物，结合常数Kd为23nM。RSC-1255对KRAS突变型癌细胞具有更⾼的选择性细胞毒性，尤其对KRASG13D和KRASG12V细胞表现最为敏感。RSC-1255能阻断溶酶体酸化(lysosomalacidification)、⾃噬(autophagy)以及巨胞饮(macropinocytosis)过程。RSC-1255可⽤于KRAS驱动的肺癌和结直肠癌研究[1]。IC50&TargetKRASG13DKRasG12V体外研究RSC-1255(249C)(1μM;1h)inhibitsV-ATPase–mediatedprotonpumpingandlysosomalacidificationinHEK293Tcells[1].RSC-1255(1μM;1h)disruptsV-ATPaseassemblybyincreasingmembrane-associatedV1subunitsinHEK293Tcells[1].RSC-1255exhibitspotentgrowth-inhibitoryactivityinhumancancercelllines,withIC50valuesof0.073μMinA549(KRAS-mutant),0.06μMinLOXIMVI(BRAFV600E),and0.022μMinMelJuso(HRASG13D/NRASQ61L)cells[1].RSC-1255(0-10μM;72h)selectivelyreducescellviabilityinKRAS-mutantmouseembryonicfibroblasts(MEFs)withthehighestsensitivityinKRASG13DandKRASG12Vcells[1].RSC-1255(1μM;2-24h)blocksautophagicflux,increasingSQSTM1/p62andLC3-IIaccumulationinA549cells[1].RSC-1255(1μM;1h)increaseslysosomalpHinKRAS^G13DMEFs,reversingtheirhighlyacidicbasallysosomalstate[1].RSC-1255(1μM;1h)inhibitsV-ATPase–dependentprotontransportinFITC-loadedlysosomes,showingthestrongestinhibitioninKRASG13DMEFs[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemERSC-1255(1μM;24h)enlargesautophagicvesiclesandblockslysosome-autophagosomefusioninKRASG13D,KRASG12VandBRAFV600EMEFs[1].RSC-1255(1μM;2h)markedlyreducesmacropinocytosislevelsinMEFs,withKRASG13Dcellsshowingthestrongestsuppression[1].RSC-1255((1μM;24h)inducesapoptosisinKRAS-mutantMEFs,withKRASG13D,KRASG12VandBRAFV600EcellsshowingthehighestAnnexinV/PIlevels[1].WesternBlotAnalysis[1]CellLine:HEK293TcellsConcentration:1μMIncubationTime:1hResult:Increasedmembrane-associatedV1subunitB2wasobserved,indicatingalteredV-ATPaseassemblyaftertreatment.WesternBlotAnalysis[1]CellLine:A549cellsConcentration:1μMIncubationTime:2,4,8,20,24hResult:Time-dependentaccumulationofSQSTM1/p62andLC3-II,indicatingautophagicfluxinhibition.CellViabilityAssay[1]CellLine:MEFKRASmutants(KRASG13D,KRASG12V,KRASG12D,KRASG12S,KRASG12C,KRASQ61L,KRASQ61R,WT)Concentration:0-10μMIncubationTime:72hResult:HighestsensitivityinKRASG13DandKRASG12VMEFswiththelowestIC50values;minimalsensitivityinWTMEFs.ApoptosisAnalysis[1]CellLine:MEFsexpressingKRASG13D,KRASG12V,BRAFV600EandotherKRASmutantsConcentration:1μMIncubationTime:24hResult:IncreasedofAnnexinV+/PI+apoptoticcells,withKRASG13D,KRASG12Vand2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEBRAFV600EMEFsshowingthestrongestapoptoticresponses.体内研究RSC-1255(249C)(10mg/kg;intraperitoneal(i.p.)injection;onceortwicedaily)significantlyinhibitstumorgrowthinKRAS-mutantlungcancerandKRAS-mutantcolorectalcancerxenograftmodelsinmice[1].AnimalModel:A549(KRASG12S)lungcancerxenograftswereestablishedinfive-week-oldathymicmice.Dosage:10mg/kgAdministration:Intraperitonealinjection(i.p.);twicedailyResult:SignificantlyreducedtumorvolumesinA549xenograft-bearingmiceduringthetreatmentperiod.IncreasedLC3-I/IIlevelsintumortissues,indicatingautophagyinhibitioninvivo.Nosignificantsystemictoxicity,withnormalbodyweight,organweightsandhematologicalparameters.AnimalModel:SW48xenograftmodelsbearingparentalorKRAS-mutantSW48cells(KRASG12D/+,KRASG12V/+,KRASG13D/+)wereestablishedinfive-six-week-oldathymicmice].Dosage:10mg/kgAdministration:Intraperitonealinjection(i.p.);2weeks.Result:SignificanttumorgrowthinhibitioninKRAS-mutantSW48xenografts,withthestrongesteffectsinKRASG13D/+andKRASG12V+tumors.MinimalresponseinparentalSW48tumors,consistentwithlowerinvitrosensitivity.Nosignificantchangesinbodyweightorsystemictoxicityduringtreatment.REFERENCES[1].TolaniB,etal.Ras-mutantcancersaresensitivetosmallmoleculeinhibitionofV-typeATPasesinmice.NatBiotechnol.2022