MA203-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors • ScreeningLibraries • Proteinswww.MedChemEMA203Cat.No.:HY-179157分子式:C₃₈H₄₅N₉O₈分子量:755.82作用靶点:PROTACs;CheckpointKinase(Chk);DNA/RNASynthesis;Apoptosis;Bcl-2Family;Caspase作用通路:PROTAC;CellCycle/DNADamage;Apoptosis储存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性MA203是一种高效且选择性的PROTAC降解剂，靶向CHK1。MA203可加速实体瘤细胞和急性白血病细胞中CHK1的CRBN依赖性蛋白酶体降解。MA203可诱导DNA复制应激。MA203可阻断细胞周期进程并诱导肿瘤细胞凋亡(apoptosis)。MA203不会损伤健康的已分化和原始造血细胞、基质细胞以及视网膜上皮细胞。MA203可用于CHK1依赖性癌症的研究[1]。IC50&TargetChk1BaxBcl-xL体外研究MA203(PROTAC41)reducesCHK1levelsby-50%at5µMinMIAPaCa-2pancreaticductaladenocarcinoma(PDAC)cellsandbindsavidlytoCHK1(97%bindingat1.0µM)[1].MA203(2µM,24h)highlysignificantlyattenuatesCHK1levelsbyupto80%and50%inHydroxyurea(HY-B0313)(HU)-treatedMIAPaCa-2andMOLT-4cells[1].MA203(2μM,3-24h)-mediatedCHK1degradationisatime-dependenteventaccompaniedbychangesinphosphorylationstateinMIAPaCa-2cells,indicatingthatdegradationenhancesDNAdamagesignals[1].MA203plusHUreducesCHK1significantlyto50%-40%ofitslevelsinuntreatedcellsinMOLT-4cells,MOLM-13cells,RS4-11cells,HCT116cellsandattenuatesCHK1levelsinMOLM-13cells[1].MA203(1-5µM,24h)dose-dependentlyattenuatesCHK1moreefficientlywhencombinedwith5µMIrinotecan(HY-16562)thanwhenusedaloneinMIAPaCa-2cells[1].MA203(0.5-10µM,24h)exhibitsasignificantlylowerconcentrationforhalf-maximumCHK1degradationwhencombinedwith2µMCytarabine(HY-13605)(DC50=387.4nM)thanwhenusedalone(DC50=3.86µM)inMOLT-4cells[1].MA203(0.5–10μM,24h)enhancesHU-inducedDNAreplicationstress,leadingtoDNAdouble-strandbreaksandreplicationcatastropheinMIAPaCa-2andMOLT-4cells[1].MA203(2μM,24-48h)+HUsignificantlyincreasestheproportionofcellsundergoingearlyandlate1/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemEapoptosisinMIAPaCa-2andMOLT-4cells[1].MA203(2µM,24h)aloneandincombinationwithHUpromotestheviabilityofdendriticcells[1].MA203(2µM,24h)substantiallyaugmentsAra-C-mediatedcelldeath,evidencedbya62%decreaseintheAra-Cconcentrationneededtokill50%ofMOLT-4cells(IC50)inMOLT-4cells[1].MA203(2µM,24h)+HUfor24hyieldsauniqueandobviousreductionofseveralkeyproteinsthatcontroltumorigenesisandDNAdamagerepair,includingtranscriptionfactor-7(TCF7),celldivisioncycle-associated-7(CDCA7),originrecognitioncomplexsubunit-1(ORC1),andWernersyndromeRecQ-likehelicase(WRN)andweaklyaugmentedRRM2levelsinMIAPaCa-2cells[1].MA203(2µM,24-48h)+HUleadstostrongerG1/Sphasearrest;inducesahigherapoptosisrate,accompaniedbyupregulationofBAX/BIManddownregulationofBCL-XL/XIAP;moresignificantlossofmitochondrialmembranepotentialandstrongercaspaseactivationinMIAPaCa-2cells[1].WesternBlotAnalysis[1]CellLine:MIAPaCa-2cells,MOLT-4cellsConcentration:2µMIncubationTime:24hResult:SpecificallydegradedCHK1,andthisdegradationisenhancedbyHU-inducedCHK1activation.DidnotaffectothercheckpointkinasesorcommonCRBNsubstrates.WesternBlotAnalysis[1]CellLine:MIAPaCa-2cellsConcentration:2µMIncubationTime:3h,6h,10h,16h,24hResult:IllustratedthatthedegradationofCHK1startedalreadyafter3hinMIAPaCa-2cells,toyielda50%-70%reductionofCHK1after10-16h.SuppressedtheHU-inducedhyperphosphorylationofCHK1atS296butaugmenteditsHU-inducedhyperphosphorylationatS345.DidnotalterCHK2levelsoverdifferenttimepoints.WesternBlotAnalysis[1]CellLine:MIAPaCa-2,MOLT-4Concentration:0.5μM,1μM,2μM,5μM,10μMIncubationTime:24hResult:SignificantlyincreasedγH2AXlevels(4.2-fold).AchievedaDmaxof92%ataDC50of1.51µMinMIAPaCa-2cells,andaDmaxof2/3 MasterofBioactiveMolecules—您身边的抑制剂大师www.MedChemE93.2%ataDC50of5.35µMinMOLT-4cells.Significant15.7-foldinductionofATMphosphorylationatS1981.ApoptosisAnalysis[1]CellLine:MIAPaCa-2cells,HCT116cells,MOLT-4cells,MOLM-13cellsConcentration:2μMIncubationTime:24h,48hResult:After48h,thepercentagesofearlyandlateapoptoticcellssignificantlyincreasedto15%and14%inMIAPaCa-2cellcultures;Asignificantriseintheearlyapoptoticcellpopulationto33%wasobserved.InHCT116cells,causedearlyandlateapoptosisweresignificantlyincreasedwhencombinedwith0.5mMHUfor48h.Anaccumulationoflateapoptoticcells(30%)occurredupontreatment.Significantlyaugmentedcellpopulationsinearlyapoptosisto19%andinlateapoptosisto15%after24hinMOLT-4cells.Inthepresenceof1mMHU,triggeredearly(48%)andlate(24%)apoptoticcelldeath.InMOLM-13cells,triggeredasignificantaccumulationofearlyapoptoticcells(33%),enhancedlateapoptosisofMOLM-13cellsto50%.Normalhumancellsdidnotexhibitanysignificantimpairmentinviabilityupontreatment.体内研究MA203(PROTAC41)(12μM,48h)significantlyinhibitstheproliferationofhumanleukemiacellsinzebrafishlarvae,andshowsnosignificanttoxicitytozebrafishlarvaeateffectivedoses[1].REFERENCESAshryR,etal.IdentificationofaProteolysis-Targeting-ChimerathatAddressesActivatedCheckpointKinase-1RevealsitsNon-CatalyticFunction