Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemESVC112Cat.No.:HY-175164分子式:C??H??BrN?O?分子量:835.74作用靶點(diǎn):Apoptosis;c-Myc作用通路:Apoptosis儲(chǔ)存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性SVC112是一種翻譯延伸(translationelongation)抑制劑，其通過(guò)阻止EF2從核糖體上的周期性解離來(lái)抑制翻譯的延伸步驟。SVC112在多種癌細(xì)胞系(急性髓系白血病(AML)、多發(fā)性骨髓瘤(Myeloma)、結(jié)直腸癌(CRC)和頭頸部鱗狀細(xì)胞癌(HNSCC)中顯示出抑制活性。SVC112優(yōu)先阻礙mRNA的核糖體加工，并減少包括Myc和Sox2在內(nèi)的CSC相關(guān)蛋白。SVC112在血液癌細(xì)胞系中誘導(dǎo)凋亡(apoptosis)，而在結(jié)直腸癌細(xì)胞系中，c-Myc的磷酸化與其對(duì)SVC112的敏感性相關(guān)。SVC112在體外可滅活HNSCC干細(xì)胞，并防止小鼠HNSCC腫瘤異種移植模型的腫瘤再生長(zhǎng)。SVC112可以用于頭頸部鱗狀細(xì)胞癌的研究[1][2]。體外研究SVC112(0-10μM,72h)showsawiderangeofgrowthinhibitionindifferentcancercelllines:acutemyeloidleukemia(AML-BDL-1,MV-4-11,HL-60andMOLM-13cells)(IC50<0.1μM),(THP-1,NOMO-1,MONO-MAC-6andU-937cells)(IC50=0.1-0.5μM),(Kasumi-3andKG-1acells)(IC50>1μM);multiplemyeloma(NCI-H929,L-363,RPMI-8226,OPM-2,U266,MM.15andMM.1Rcells)(IC50<0.1μM),(LP-1cells)(IC50=0.1-0.5μM);colorectalCancer(SW48,RKO,HCT116,WiDrandCL-34cells)(IC50<0.1μM),(HT29,MDST8,COLO201,GP2D,NCI-H747,SNU70,SW837andSW403cells)(IC50=0.1-0.5μM),(DLD-1,T84,KM-12C,SW948,Q-11,HCT-15andSW48cells)(IC50>1μM);headandnecksquamouscellcarcinoma(FaDu)(IC50<0.1μM)[1].SVC112(1μM,2h)inhibitsdenovoproteinsynthesisinMV-4-11,NCI-H929,HCT116,FaDu,DLD-1andSW948cells[1].SVC112(1μM,6-24h)inducesapoptosisinAMLandMyelomacelllines(AML-EOL-1,MV-4-11,OCI-AML-3,NCI-H929,RPMI-8226andU226B1cells),butnotinCRCandHNSCCcelllines(HCT116andFaDucells)[1].SVC112(1μM,6h)exhibitsdifferentialsensitivityacrosscolorectalcancercelllines(DLD-1andSW948cells)thatcorrelateswithc-Mycstatus[1].SVC112(0.2-0.4μM)exhibitsgenerallyenhancedgrowthinhibitoryeffectswiththeadditionofUlixertinib(HY-15816)(1μM)[1].SVC112(5-1000nM,2h)inhibitsproteinsynthesis,proliferation,andenhancesradiationeffectsinDet562andFaDuHNSCCcells[2].SVC112(0.1-1000nM)inhibitsinvitrocap-independenttranslationofcaplessluciferasemRNAusingrabbitreticulocytelysates(IC50=81nM)[2].SVC112(1-10000nM)shows1/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEantiproliferativeeffectsin036C,067C,049C,and013C，withIC50sof3.8nM,9.3nM,24.1nM,and50.5nM,respectively[2].SVC112(10-1000nM,10days)decreasessphereformationby013C,036C,049Cand067CHNSCCcelllines[2].SVC112(100nM,0-24h)depletesproteinsbyinfluencingtranslationbutnottranscriptionandinhibitstranslationmorepotentlyin013C,036C,049Cand067CHNSCCcelllinesthanautologousnon-cancercells[2].SVC112(100-1000nM,6-48h)inducesreversibleproteindepletionwhileexertinglonger-lastingeffectsoncancerstemcell(CSC)properties[2].SVC112(100-1000nM,24h)showsanti-spheringeffectsin013C,036C,067Cand049CcellswhicharerescuedbyexogenousSox2expression[2].SVC112(100nM,12-24h)enhancestheeffectsofradiationbydelayingDNArepairin013C,036C,067Cand049Ccells[2].ApoptosisAnalysis[1]CellLine:MV-4-11,NCI-H929,HCT116andFaDucellsConcentration:1μMIncubationTime:6hResult:InducedrobustapoptosisinMV-4-11andNCI-H929cells,butnotinHCT116andFaDucells.WesternBlotAnalysis[1]CellLine:AML-EOL-1,MV-4-11,MOLM-13,OCI-AML-3,NCI-H929,RPMI-8226,U226B1,THP-1,NOMO-1,Kasumi-3,HCT116andFaDucellsConcentration:1μMIncubationTime:6,24hResult:InducedPARPcleavageconcomitantlywithdepletionofMCL-1andc-MycinAMLandMyelomacelllines(AML-EOL-1,MV-4-11,OCI-AML-3,NCI-H929,RPMI-8226andU226B1cells),butnotinCRCandHNSCCcelllines(HCT116andFaDucells).ShowedlittlesignofPARPcleavagedespitelossoftheunstableproteinsMCL-1andc-Myc.ApoptosisAnalysis[2]CellLine:Det562andFaDuHNSCCcellsConcentration:5,20,50,100,200,500,1000nMIncubationTime:2hResult:DepletedMycandCyclinD1inDet562andFaDuHNSCCcells.體內(nèi)研究SVC112(60mg/kg,i.p.,oncedaily,3weeks)showsefficacyinMV-4-11,AML-EOL-1andHCT116cellsxenograftedtumorsinmice[1].SVC112(15mg/kg,i.p.,oncedaily,3weeks)inhibitstumorgrowthinDLD12/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEcellsxenograftedtumorsinmicewhencombinedwithUlixertinib(HY-15816)[1].SVC112(60mg/kg,i.p.,fourtimesweekly,28days)aloneandwithradiationinhibitstumorgrowthinCUHN036,CUHN047,CUHN004,andCUHN013PDXmodels[2].AnimalModel:107MV-4-11cellspermousemixed1:1withMatrigelMatrixin100μLtotalvolumewereinoculatedbysubcutaneousinjectionintotherighthindflankofBALB/cnudemice(6-8weeksoldfemales);5×106MV-4-11cellspermousein100μLPBSwereinoculatedintothetailveinofNOGmice(6-8weeksoldfemales);1×106AML-EOL-1,MV-4-11or5×105HCT116cellspermousemixed1:1withMatrigelin100μLtotalvolumewereinoculatedbysubcutaneousinjectionintotherighthindflankofnu/numice(5-8weeksoldfemales)[1]Dosage:60mg/kgwithQDX5(i.p.fivetimesweekly)Administration:i.p.,oncedailyfor3weeksResult:Showedsignificanttumorgrowthcontrolinallthreemodels.ProvidedsignificantsurvivalbenefitinmicebearingMV-4-11andAML-EOL-1xenografts.Showednosignificantchangesinbodyweight.AnimalModel:1×106DLD-1cellspermousemixed1:1withMatrigelin100μLtotalvolumewereinoculatedbysubcutaneousinjectionintotherighthindflankofnu/numice(5-8weeksoldfemales)[1]Dosage:15mg/kgcombinedwithUlixertinib(50mg/kg)Administration:i.p.,oncedailyfor3weeksResult:ReducedtumorgrowthsignificantlycomparedtovehiclecontrolswhencombinedwithUlixertinibwhereasthesingledrugtreatmentshadnosignificanteffects.AnimalModel:Tumorpieceswereimplantedonbothflanksof6to10-week-oldfemaleAthymicNude-Foxn1numiceDosage:60mg/kgorcombinedwithradiation(3Gy)Administration:i.p.twiceweeklyfor28daysResult:SuppressedgrowthinCUHN036(T/C=0.45)andCUHN047(T/C=0.37)alone.InhibitedgrowthinCUHN047(T/C=?0.02),CUHN036(T/C=0.08),andCUHN004(T/C=0.19)whencombinedwithradiation.IncreasedinhibitionofFaDuxenograftswhencombinedwithradiation(2Gytwiceweekly)andCisplatin(HY-17394)(1mg/kgweekly).SuppressedMycinC