Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemENP1192Cat.No.:HY-178360CASNo.:2966791-41-1分子式:C??H??N?O?S分子量:734.87作用靶點(diǎn):PROTACs;HistoneAcetyltransferase;HIF/HIFProlyl-Hydroxylase;PD-1/PD-L1;PTEN作用通路:PROTAC;Epigenetics;MetabolicEnzyme/Protease;Immunology/Inflammation;PI3K/Akt/mTOR儲存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性NP1192是一種高效、選擇性的PROTACNAT10降解劑，可降低癌細(xì)胞中NAT10蛋白的表達(dá)并抑制ac4C修飾。NP1192通過破壞NAT10/HIF-1α/PD-L1軸，實(shí)現(xiàn)對缺氧驅(qū)動的糖酵解和免疫抑制的雙重抑制，在體外和體內(nèi)均展現(xiàn)出卓越的抗腫瘤功效，并與抗PD-L1聯(lián)合產(chǎn)生協(xié)同作用。NP1192可用于卵巢癌、宮頸癌、膠質(zhì)母細(xì)胞瘤相關(guān)研究。(藍(lán)色:CRBN配體(HY-148834);黑色:連接子;粉色:NAT10配體(HY-16706))[1]。IC50&TargetNAT10體外研究NP1192(0-20μM,24-48h)inducesNAT10degradationinSiHa(human)andU14(murine)CCacelllinesinadose-andtime-dependentmanner,throughtheubiquitin-proteasomesystem(UPS)ratherthanvialysosomalpathways[1].NP1192(36h)inhibitscervicalcancer(SiHa)cellgrowthwithanIC50of7.814μM(76.2μMinresistantcells)andadditionallyshowsdose-dependentefficacyinorganoids,withIC50valuesof9.947,3.048,and13.76μMforovarian(OV),cervical(CESC),andglioblastoma(GBM)models,respectively[1].NP1192(20μM,0-72hand2weeks)significantlyreducescellviability,inducescellcyclearrest,andsuppressesinvasionandclonogenicgrowthinCCacells[1].NP1192(0.195-50μM,1-8days)inducesapronouncedreductioninorganoidsizeandnumberacrosstumormodels(ovarian,cervical,andglioblastoma),whilethecorrespondingnormalorganoidsremainedunaltered,indicatingminimalcytotoxicitytononmalignanttissues[1].NP1192(20μM,36h)reprogramsthehypoxictumormicroenvironment(TME)andmetabolisminCCacellsbydegradingNAT10andtherebyimpairingHIF-1αexpression,whichdisruptsglycolysisasevidencedbyreducedglucoseuptakeandlactateproductionalongsideelevatedATPlevels[1].1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEWesternBlotAnalysis[1]CellLine:SiHa,U14,andHFF-1cellsConcentration:0,1.25,2.5,5,10and20μMIncubationTime:24,36and48hResult:LedtoasubstantialdepletionoftotalNAT10proteininSiHa(human)andU14(murine)CCacelllinesinaadose-andtime-dependentmanner.Induceddegradationratesof28%,32%,40%,and43%inSiHacellsatconcentrationsof1.25,2.5,5,and10μM,respectively,withamaximumof69%degradationat20μMafter36handonly20%degradationafter24h.Ledtoanearly70%reductionintheNAT10proteincontentinmurineU14cervicalcellsafter36h.Didnotexhibittheclassicalhookeffectevenatconcentrationsashighas20μM.FailedtodegradeNAT10significantlywhenco-treatedwithMG132(HY-13259),whereasBafilomycinA1(HY-100558)exertednodiscernibleeffectonitsdegradationefficacy.SubstantiallyinducedminimalcytotoxicityinnonmalignantHFF-1cellswithlowNAT10expression.DecreasedHIF-1αproteinlevels.Reversedtheinductionofhypoxia-relatedgenesunderhypoxicconditions,suchasHIF1AandPD-L1,atbothmRNAandproteinlevels.CellProliferationAssay[1]CellLine:SiHacellsandNAT10-KDSiHacellsConcentration:20μMIncubationTime:2weeksResult:Ledtoasubstantialdecreaseincolonyformationcapacity,withthemagnitudeofinhibitionbeingonlysecondtothatinNAT10-knockdowncells.CellInvasionAssay[1]CellLine:SiHacellsandNAT10-KDSiHacellsConcentration:20μMIncubationTime:36hResult:Substantiallyhinderedcellinvasionwithasignificantdecreaseinthenumberofcellscrossingthebasementmembrane.體內(nèi)研究NP1192(25mg/kg,i.p.,every2daysforaweek)synergizeswithanti-PD-L1toinhibittumorgrowth,2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEsuppressglycolysis,andenhanceCD8+TeffcellimmunityinU14-lucxenograftmousemodel[1].AnimalModel:FemaleC57BL/6Jmice(6-8weeksold)subcutaneouslyinjectedwithU14-luccells[1]Dosage:25mg/kgAdministration:i.p.,every2daysforaweekResult:SignificantlyreducedtumorvolumeandtumorburdencomparedtoDMSOat25mg/kg.Significantlyinhibitedtumorgrowthwhencombinedwithanti-PD-L1antibody(2.5mg/kg).Showedthemostpronouncedreduction(>80%)intumorlactatelevelswhencombinedwithanti-PD-L1antibody(2.5mg/kg).1?F-FDGPET–CTimagingrevealedminimalmetabolicuptakewhencombinedwithanti-PD-L1antibody,suggestingeffectivesuppressestumormetabolicactivity.EnhancedtheCD8+Teffcellpopulation,reprogramstheTME,andpotentiatesantitumorimmunitywhencombinedwithanti-PD-L1blockade.Didnotcausesignificantweightlossorsystemictoxicitybothaloneandincombination.REFERENCESAo,K.,etal.TargetedNAT10DegradationbyPROTACNP1192SuppressesHypoxia-AdaptiveGlycolysisandReinvigoratesCD8+EffectorT-CellFunctionforSynergisticCancerImmunot