Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemESD-436Cat.No.:HY-169360CASNo.:2497585-50-7分?式:C??H??F?N?O??PS分?量:1248.2作?靶點(diǎn):PROTACs;STAT作?通路:PROTAC;JAK/STATSignaling;StemCell/Wnt儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性SD-436?種?選擇性和?效的STAT3PROTAC降解劑(DC50為0.5μM)，對(duì)STAT3、STAT1、STAT4、STAT5和STAT6的IC50分別為19nM、270nM、360nM、>10μM和>10μM。SD-436可促進(jìn)STAT3的泛素化和降解，且誘導(dǎo)腫瘤消減。SD-436可?于腫瘤研究，例如??病和淋巴瘤(粉紅：STAT3配體(HY-169361)；藍(lán)?：E3連接酶配體(HY-43722)；??：連接?(HY-147052)[1]。IC50&TargetCereblonSTAT3STAT1STAT519nM(IC50)270nM(IC50)>10μM(IC50)STAT6>10μM(IC50)體外研究SD-436(4daytreatment)inhibitsthegrowthofMOLM-16leukemiacellline,SU-DHL-1andSUP-M2lymphomacelllines,withIC50of0.038μM(MOLM-16),0.43μM(SU-DHL-1)and0.39μM(SUP-M2)[1].SD-436(0.1nM-40μM,4or20h)selectivelyreducesthelevelsofSTAT3proteininhumanPBMCs,SU-DHL-1andMOLM-16cellline(4h)[1].SD-436(0.1nM-40μM,20h)effectivelyreducesthelevelsofthemutatedSTAT3protein(STAT3K658R)inadose-dependentmannerinthePfeiffercellline,withaDC50valueof2.5nM[1].SD-436showsexcellentstabilityinmouse,rat,dog,monkeyandhumanplasma,withT1/2of>120min[1].SD-436hasnosignificantinhibitionofthehumanether-a-go-go-relatedgenepotassiumchannels(hERGinhibition:1.3%for3μMand1.1%for30μM)[1].WesternBlotAnalysis[1]1/2MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECellLine:PBMC,MOLM-16,SU-DHL-1andPfeifferConcentration:0.1nM,0.5nM,2.5nM,13nM,64nM,320nM,1600nM,8000nM,40000nMIncubationTime:20hResult:ReducedthelevelsofSTAT3proteininhumanPBMCsandSU-DHL-1cellline,withDC50of0.1nMand10nM,respectively.Achievednearcompletedegradationat320nMwithmerelya4htreatmenttimeintheMOLM-16cellline.ReducedthelevelsofthemutatedSTAT3proteininadose-dependentmannerinthePfeiffercellline,withaDC50valueof2.5nM.ShowedhighselectivityforSTAT3overotherSTATproteins.體內(nèi)研究SD-436(5mg/kg,i.v.,single)effectivelyinducesrapid,complete,anddurabledepletionofSTAT3inmousenative(liverandspleen)andMOLM-16xenografttumortissues[1].SD-436(5-25mg/kg,i.v.)showsantitumoractivityinleukemiaandlymphomaxenograftmodelsinmice[1].PharmacokineticsofSD-436inmice,rats,anddogsSpeciesIVdose(mg/kg)t1/2(h)Cmax(ng/mL)AUC(0-t)(h×ng/mL)Vz(L/kg)CI(mL/min/kg)Cl(%HBF)ICRmouse522.1130,185859,2230.100.0510.1%SDrat51.082,62659,48%beagledog12.3886110,6990.291.52.7%AnimalModel:MOLM-16acuteleukemiaxenograftmodelandtheSU-DHL-1lymphomaxenograftmodelinSCIDmice(injectedsubcutaneouslywith3×106MOLM-16cellsor5×106SU-DHL-1cells)[1]Dosage:5,10,20mg/kg(MOLM-16);10,25mg/kg(SU-DHL-1)Administration:Intravenousinjection(i.v.);onceaweek,fourweeks(MOLM-16:5,10,20mg/kg;SU-DHL-1:10,25mg/kg)ortwiceaweek,fourweeks(SU-DHL-1:25mg/kg)Result:ShowedthatSD-436at5mg/kgwasabletoachieveamaximumof76%tumorregressionintheMOLM-16leukemiaxenograftmodel.Inducedcompletetumorregressionat10and20mg/kgintheMOLM-16leukemiaxenograftmodel.Achievedcompleteandlong-lastingtumorregressionintheSU-DHL-1xenograftmodelat25mg/kgweeklydosingschedule.REFERENCES[1].Xu,etal.DiscoveryofSD-436:APotent,HighlySelectiveandEfficaciousSTAT3PROTACDegraderCapableofAchievingCompleteandLong-LastingTumorRegression.Journalofmedicinalchemistry.2024,67(22),20495–20513.McePdfHeight2/2MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECaution:Prod