Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemESMU-037Cat.No.:HY-178391分?式:C??H??ClF?N?O分?量:523.02作?靶點(diǎn):ROSKinase;p38MAPK;ERK;Apoptosis作?通路:ProteinTyrosineKinase/RTK;MAPK/ERKPathway;StemCell/Wnt;Apoptosis儲存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性SMU-037?種?服有效的選擇性ROS1抑制劑，其作?強(qiáng)效(IC??=6.8nM)，且能穿透?腦屏障。SMU-037對ALK的選擇性約為25倍，且對G2032R耐藥突變表現(xiàn)出卓越的敏感性。SMU-037能夠抑制ROS1及其下游MAPK-ERK信號通路的磷酸化，進(jìn)?引起細(xì)胞周期阻滯與細(xì)胞凋亡(apoptosis)。SMU-037在?下移植瘤和顱內(nèi)轉(zhuǎn)移瘤??模型中均能抑制腫瘤?長。SMU-037可?于??細(xì)胞肺癌(NSCLC)的相關(guān)研究[1]。體外研究SMU-037(compound9y)exhibitsrobustactivityagainstA549(IC50=0.9μM),HCC-78(IC50=1.1μM)andNCI-H3122cells(IC50=1.1μM),andinhibitsBa/F3ROS1G2032RandBa/F3ROS1L2026RcellswithIC50valuesof8.9and32.0nM[1].SMU-037(0.001-3μM,8h)attenuatesphosphorylationofROS1andthekeydownstreamMAPK-ERKsignalingpathwayinadose-dependentmannerinmultipleBa/F3andA549cells[1].SMU-037(0-100nM,48h)arrestscellcycle(G0/G1phaseinROS1WTcellsandG2/MphaseinROS1G2032Rcells)andinducesapoptosisinbothBa/F3-ROS1WTandBa/F3-ROS1G2032Rcells[1].WesternBlotAnalysis[1]CellLine:Ba/F3-ROS1WT,Ba/F3-ROS1G2032R,Ba/F3-ROS1L2026MandA549-ROS1G2032RcellsConcentration:1,10,100,and10000nM,0.1,0.3,1and3μMIncubationTime:8hResult:ExhibitedremarkableinhibitoryeffectsonROS1G2032Rphosphorylationattheconcentrationof1000nM.SlightlyinhibitedthedownstreamMAPK-ERKsignalingpathwayattheconcentrationof1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE1000nM,withefficacycomparabletoCabozantinib(HY-13016).LedtoattenuatedphosphorylationofROS1andthekeydownstreamMAPK-ERKsignalingpathwayinadose-dependentmannerinBa/F3-ROS1WTandBa/F3-ROS1L2026Mcells,comparabletoCrizotinib(HY-50878).ExhibitedamarkedsuppressionofROS1phosphorylationataconcentrationof1μMinA549-ROS1G2032Rcells.CellCycleAnalysis[1]CellLine:Ba/F3-ROS1WTandBa/F3-ROS1G2032RcellsConcentration:0,10,30,and100nMIncubationTime:48hResult:SignificantlyincreasedthepercentageofROS1WTcellsintheG0/G1phase.CausedapredominantG2/MphaseaccumulationinROS1G2032Rcells.TheG0/G1phaseofROS1G2032Rcellsincreasedfrom57.10%(control)to60.71%,72.97%,and85.28%,respectively.TheG2/MphaseofROS1G2032Rcellsincreasedfrom6.14%(control)to6.98%,14.42%,and27.16%,respectively.ApoptosisAnalysis[1]CellLine:Ba/F3-ROS1WTandBa/F3-ROS1G2032RcellsConcentration:0,10,30,and100nMIncubationTime:48hResult:Inducedadose-dependentincreaseinapoptosis.ApoptoticratesinROS1WTcellsrosefrom13.12%(control)to16.95%,31.50%,and91.87%.ApoptoticratesinROS1G2032Rcellsincreasedfrom19.85%(control)to20.46%,28.03%,and54.60%.體內(nèi)研究SMU-037(15,30and60mg/kg,i.g.,q.d.for14days)showspotenttumorgrowthinhibitioninxenograft/brainmetastasismousemodels[1].AnimalModel:MaleBalb/cnudemice(16-20g)injectedwithBa/F3CD74-ROS1G2032Rcells[1]Dosage:15,30and60mg/kgAdministration:i.g.,q.d.for14daysResult:EffectivelysuppressedBa/F3tumorgrowthinadose-dependentmanner,withtumor2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEgrowthinhibition(TGI)valuesof118,140,and156%,respectively.Showednosignificantbodyweightreductionandnomorphologicalchangesorsideeffectsinheart,liverandkidney.SignificantlyinhibitedROS1phosphorylationintumortissue,demonstratingitson-targeteffectinvivo.Inducedprominentalterationsinthemorphologicalcharacteristicsoftumorcells,includingcellularcontraction,agglutination,andmarginalizationofnuclearchromatin.SignificantlyreducedexpressionleveloftheKi-67protein,indicatingstronganti-proliferativeactivity.AnimalModel:MaleBalb/cnudemice(16-20g)injectedwithA549-ROS1G2032Rcells[1]Dosage:15,30and60mg/kgAdministration:i.g.,q.d.for14daysResult:Demonstratedsignificanttumorregressionatdosesof30mg/kgand60mg/kg,comparabletothepositivecontrolLorlatinib(HY-12215,30mg/kg).AnimalModel:MaleBalb/cnudemice(16-20g)injectedwithluciferase-transducedA549-ROS1G2032Rcells[1]Dosage:30and60mg/kgAdministration:i.g.,q.d.for14daysResult:Prominentlyreducedtumorload(asmeasuredusingphotonflux)inthebrainwithoutobviousbodyweightloss.Couldpenetrateblood-brainbarrier.REFERENCES[1].LiuS,etal.Discoveryofnovel3-BenzyloxyaminopyridinesasorallyavailableandintracraniallyactiveselectiveROS1inhibitorsforcombatingtheresistantROS1G2032Rmutation.EurJMedCh