Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEMA191Cat.No.:HY-175273分子式:C??H??N??O?S分子量:1088.32作用靶點(diǎn):PROTACs;FLT3;HSP;ERK;STAT;Akt;Apoptosis作用通路:PROTAC;ProteinTyrosineKinase/RTK;CellCycle/DNADamage;MetabolicEnzyme/Protease;MAPK/ERKPathway;StemCell/Wnt;JAK/STATSignaling;PI3K/Akt/mTOR;Apoptosis儲(chǔ)存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性MA191是一種FLT3PROTAC降解劑。MA191可消除因絲裂原活化激酶反彈激活而產(chǎn)生的FLT3抑制劑耐藥性。MA191通過一種需要VHL、Neddylation和BIM的機(jī)制介導(dǎo)FLT3-ITD的快速降解。MA191在誘導(dǎo)細(xì)胞凋亡(apoptosis)之前降低FLT3-ITD水平。MA191可抑制斑馬魚體內(nèi)AML細(xì)胞的增殖。MA191可用于急性髓系白血病(AML)的研究。(粉色：FLT3配體：(HY-175311)，藍(lán)色：E3連接酶CRBN配體(HY-112078)，黑色：連接子，E3連接酶配體-接頭偶聯(lián)物：(HY-175312))[1]。體外研究MA191(0-100nM,24-72h)inhibitsthegrowthofMV4-11andMOLM-13cellswithIC50valuesbetween9.6and11nM[1].MA191(50nM,6-24h)inhibitsautophosphorylationofFLT3(pY591)andphosphorylationofERK1/ERK2,STAT5andAKTinMV4-11andMOLM-13cells[1].MA191(10-50nM,16-24h)decreasesFLT3-ITDandHSP110dose-andtime-dependentlyinMV4-11cells[1].MA191(0-100nM,6-24htreatment)inducesBIM-dependentandneddylation-dependentdegradationofFLT3-ITDinMV4-11cells,demonstratingDC50valuesof10.5nMat16hand10nMat24h[1].MA191(0-1000nM,24-48h)inducesapoptosisofculturedandprimaryAMLcellswithFLT3-ITDanddoesnotaffectnormalimmunecells,hematopoieticstemcells,andprogenitorcells[1].MA191(50-200nM,24-72h)breaksmechanismsofFLT3inhibitorresistanceofAMLcells[1].WesternBlotAnalysis[1]CellLine:MV4-11andMOLM-13cells1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEConcentration:50nMIncubationTime:6,24hResult:InhibitedtheautophosphorylationofFLT3(pY591)andphosphorylationofERK1/ERK2,STAT5andAKT.DecreasedtheFLT3-ITDlevelsafter24h,whereasinRS4-11,FLT3waslessaffected.Increasedthelevelofcaspase-3.WesternBlotAnalysis[1]CellLine:MV4-11cells,BIM-KD-MV4-11cellsandVHL-KD-MV4-11cellsConcentration:10,20,50nMIncubationTime:6,16,24hResult:DegradedFLT3-ITDinMV4-11cellswhichwasinhibitedinBIM-KD-MV4-11cells.DegradedHSP110,HSP70,HSP27,andHSP90.InhibitedthephosphorylationofFLT3-ITD.AttenuatedphosphorylatedSTAT5dose-andtime-dependently.Showedatime-anddose-dependentaccumulationofactivecaspase-3andBIM-ELafter16h.RescuedthedegradationofFLT3incellswithaKDofVHL.ApoptosisAnalysis[1]CellLine:MV4-11andMOLM-13cellsConcentration:100,200nMIncubationTime:24,72hResult:DidnotinduceapoptosisinRS4-11aftera72-htreatment.InMV4-11cellcultures,thedeathratewasnearly100%andinthecaseofMOLM-13cellculturesitwas50%.InducedcelldeathinMOLM-13,MOLM-13-RESandMOLM-13-RES-AC.體內(nèi)研究MA191(200nM,48h,singledose)haltsAMLcellproliferationwithoutsignificanttoxicityinDanioreriolarvaemodel[1].AnimalModel:MV4-11cellsatdensityof1×106cells/mLwereinjectedintotheyolksacofzebrafishwild-typeABlineembryosonday2postfertilization[1].Dosage:200nMAdministration:48h2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEResult: HaltedAMLcellproliferation.Showednosignificanttoxicity.REFERENCESMelisaHalilovic,etal.RapidproteasomaldegradationofmutantfelineMcDonoughsarcoma-liketyrosine2kinase-3overcomestyrosinekinaseinhibitorresistanceofacutemyeloidleukemia3cells.McePdfHeightCaution:Producthasnot