AS-99-free-base-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEAS-99freebaseCat.No.:HY-141429CASNo.:2323623-93-2分?式:C??H??F?N?O?S?分?量:593.68作?靶點(diǎn):HistoneMethyltransferase;Apoptosis作?通路:Epigenetics;Apoptosis儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性AS-99?創(chuàng)的、有效的、選擇性的ASH1L組蛋?甲轉(zhuǎn)移酶抑制劑(IC50=0.79μM,Kd=?0.89?μM)，具有抗??病活性。AS-99在體內(nèi)阻斷細(xì)胞增殖，誘導(dǎo)細(xì)胞凋亡(apoptosis)和分化，下調(diào)MLL融合靶因，減輕??病。IC50&Target0.79?μM(ASH1Lhistonemethyltransferase)[1]體外研究AS-99istestedagainstapanelof20histonemethyltransferases,includingNSD1,NSD2,NSD3,andSETD2.NOsignificantinhibitionisobservedat50?μMofAS-99onanyofthetestedhistonemethyltransferases,indicatingover100-foldselectivitytowardsASH1L[1].AS-99showsaseveralfoldweakereffectontheproliferationofleukemiacellswithoutMLL1translocations,suchasSET2andK562,withnoorlimitedeffectsat10?μMorhigherconcentrations[1].AS-99(1-8μM;7days)alsoinducesapoptosisintheMLLleukemiacells,butnotintheK562cells,asassessedbythequantificationoftheAnnexinVpositivecells[1].AS-99suppressesMLLfusiondriventranscriptionalprograms[1].AS-99resultsinareducednumberofH3K36me2peakswhencomparedtotheDMSO-treatedcells[1].RT-PCR[1]CellLine:MOLM13cellsConcentration:2-6μMIncubationTime:7days1/2MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEResult:Ledtoadose-dependentdownregulationofcanonicalMLLfusiontargetgenesrequiredforleukemogenesisincludingMEF2C,DLX2,FLT3,andHOXA9.體內(nèi)研究AS-99(30?mg/kg;i.p.;q.d.,treatedfor14consecutivedays)reducesleukemiaburdeninmice[1].AS-99isusedforinvivostudiesinmice,whichrevealsfavorableexposureinplasmauponi.v.andi.p.administration(AUC?=?9701?hr*ng/mLand10,699?hr*ng/mL,respectively),suitablehalf-life(~5–6?h)andCmax?>10?μM[1].AnimalModel:8-to10-weekoldfemaleNSGmice(bearingMV4;11cells)[1]Dosage:30?mg/kgAdministration:I.p.;q.d.,treatedfor14consecutivedaysResult:ReducedtheleukemiaburdeninthexenotransplantationmousemodelofMLLleukemiawithoutaffectingbloodcountsinnormalmice.REFERENCES[1].DavidS.Rogawski,JingDeng,HaoLi,TomaszCierpicki,JolantaGrembecka,etal.Discoveryoffirst-in-classinhibitorsofASH1Lhistonemethyltransferasewithanti-leukemicactivity.NatCommun.2021May14;12(1):2792.McePdfHeightCaution:Producthasnotbeenfullyvalidatedformedicalapplications.For