Simmiparib-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemESimmiparibCat.No.:HY-115552CASNo.:1551355-46-4分?式:C??H??F?N?O?分?量:486.42作?靶點(diǎn):PARP作?通路:CellCycle/DNADamage;Epigenetics儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性Simmiparib?種?效且具有?服活性的PARP1和PARP2抑制劑，IC50分別為1.75nM和0.22nM。Simmiparib對(duì)PARP1/2的抑制作?強(qiáng)于其母體化合物Olaparib(HY-10162)。在同重組修復(fù)(HR)缺陷細(xì)胞中，Simmiparib誘導(dǎo)DNA雙鏈斷裂(DSB)積累和G2/M阻滯，從?誘導(dǎo)細(xì)胞凋亡(apoptosis)。Simmiparib在細(xì)胞和裸?移植瘤模型中都表現(xiàn)出顯著的抗癌活性。IC50&TargetPARP1PARP20.74nM(IC50)0.22nM(IC50)體外研究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?邊的抑制劑?師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.體內(nèi)研究Simmiparib(2,4and8mg/kg;p.o.;qd,for14days)inhibitsthegrowthoftumorinV-C8(BRCA2-/-)andMDA-MB-436(BRCA2-/-)xenograftmicemodels[1].2/3MasterofBioactiveMolecules—您?邊的抑制劑?師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