Simmiparib-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemESimmiparibCat.No.:HY-115552CASNo.:1551355-46-4分⼦式:C₂₃H₁₈F₄N₆O₂分⼦量:486.42作⽤靶点:PARP作⽤通路:CellCycle/DNADamage;Epigenetics储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性Simmiparib⼀种⾼效且具有⼝服活性的PARP1和PARP2抑制剂，IC50分别为1.75nM和0.22nM。Simmiparib对PARP1/2的抑制作⽤强于其母体化合物Olaparib(HY-10162)。在同重组修复(HR)缺陷细胞中，Simmiparib诱导DNA双链断裂(DSB)积累和G2/M阻滞，从⽽诱导细胞凋亡(apoptosis)。Simmiparib在细胞和裸⿏移植瘤模型中都表现出显著的抗癌活性。IC50&TargetPARP1PARP20.74nM(IC50)0.22nM(IC50)体外研究Simmiparib(0-10μM;3days)exhibitsanti-proliferativeactivityagainstvariouscancercells[1].Simmiparib(0-10μM;48h)inducestypicalG2/MarrestinCapan-1cells[1].Simmiparib(0.1-2μM;24h)inducesapoptosisinMDA-MB-436andV-C8(BRCA2-/-)cells,andincreasesdose-dependentlythelevelsofγH2AX[1].Simmiparib(1-10μM;48hor72h)increasesthephosphorylationlevelsofChk1andChk2andtheproteinlevelsofp-CyclinB1(S147),CyclinB1,p-CDK1(Y15)andCDK1[1].CellProliferationAssay[1]CellLine:VariouscancercellsharboringdeficientBRCA1,BRCA2,PTENandEWS-FLI1Concentration:0-10μMIncubationTime:3daysResult:Exhibitedanti-proliferativeactivityagainstMDA-MB-436(BRCA1-/-),RD-ES(EWS-FLI1),1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEDoTc2-4510(BRCA2-/-),Capan-1(BRCA2-/-)andU251(PTEN-/-)withIC50sof0.2nM,4.6nM,20nM,21nMand36nM,respectively.CellCycleAnalysis[1]CellLine:Capan-1cellsConcentration:0,1,3and10μMIncubationTime:48hResult:InducedtypicalG2/Marrestinaconcentration-dependentmanner.ApoptosisAnalysis[1]CellLine:MDA-MB-436Concentration:0.1and1μMIncubationTime:24hResult:Ledto39.64%and42.98%apoptosisat0.1and1μM,respectively.Increaseddose-dependentlythelevelsofγH2AX.ApoptosisAnalysis[1]CellLine:V-C8(BRCA2-/-)Concentration:0.5and2μMIncubationTime:24hResult:Causedmorethan57%apoptosis.WesternBlotAnalysis[1]CellLine:Capan-1Concentration:1and10μMIncubationTime:48hor72hResult:IncreasedthephosphorylationlevelsofChk1andChk2butdidnotchangethelevelsofthecorrespondingtotalproteins.Increasedtheproteinlevelsofp-CyclinB1(S147),CyclinB1,p-CDK1(Y15)andCDK1.体内研究Simmiparib(2,4and8mg/kg;p.o.;qd,for14days)inhibitsthegrowthoftumorinV-C8(BRCA2-/-)andMDA-MB-436(BRCA2-/-)xenograftmicemodels[1].2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESimmiparib(10and50mg/kg;p.o.;qd,for42days)inhibitsthegrowthofBRCA1-mutatedbreastcancerinxenograftmicemodel[1].AnimalModel:FemaleBALB/cAnudemice(SubcutaneouslyinjectedwithBRCA2-/-V-C8cellsandBRCA2-/-MDA-MB-436cells)[1]Dosage:2,4and8mg/kgAdministration:p.o.;qd,for14daysResult:ApparentlyinhibitedthegrowthoftheV-C8tumorwithaninhibitionrateof74.53%at8mg/kg.SuppressedthegrowthoftheBRCA1-deficientMDA-MB-436xenograftsinadose-dependentmannerwithitsaverageinhibitionratesof64.93,82.98and85.79%at2,4and8mg/kg.Didnotcausesignificantlossofbodyweight.AnimalModel:FemaleBALB/cAnudemice(SubcutaneouslyinjectedwithcancercellsderivedfromBRCA1-mutatedBR-05-0028breastcancertissue)[1]Dosage:10and50mg/kgAdministration:p.o.;qd,for42daysResult:Eliciteddose-dependentgrowthinhibitionwiththeinhibitionrateof76.73%and93.82%at10mg/kgand50mg/kg,respectively.REFERENCES[1].YuanB,etal.Poly(ADP-ribose)polymerase(PARP)inhibitionandanticanceractivityofsimmiparib,anewinhibitorundergoingclinicaltrials.CancerLett.2017Feb1;386:47-56.McePdfHeightCaution:Pr