Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemECSF1R-IN-22Cat.No.:HY-162415CASNo.:2760585-35-9分?式:C??H??N?O?分?量:392.41作?靶點:c-Fms;Apoptosis作?通路:ProteinTyrosineKinase/RTK;Apoptosis儲存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性CSF1R-IN-22(CompoundC19)?服有效的CSF-1R選擇性的抑制劑(IC50+T細胞的浸潤，增強anti-PD-1抗腫瘤免疫反應，誘導細胞凋亡。CSF1R-IN-22可以有效地將M2型的腫瘤相關巨噬細胞重編程為M1表型，并通過誘導CD8+T細胞募集到腫瘤中并減少免疫抑制性Tregs/MDSCs的浸潤來重塑腫瘤相關巨噬細胞[1]。體外研究CSF1R-IN-22(0-2500nM;1h)significantlyinhibitstheactivationofCSF-1RsignalingpathwayinBMDMscells[1].CSF1R-IN-22(30-100nM;24h)efficientlyreprogramsM2-typemacrophagestoM1-typemacrophagesinBMDMsandHMDMscells[1].CSF1R-IN-22(10-100nM;20h)processedM2-typemacrophagesupernatantssignificantlyinhibitsMC-38andCT-26cellviability[1].WesternBlotAnalysis[1]CellLine:BMDMscellsConcentration:10,30,100nMIncubationTime:1hResult:Dose-dependentlyinhibitedthephosphorylationofCSF-1RanditsdownstreamsignalingmediatorsAKTandmTORC1.ApoptosisAnalysis[1]1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECellLine:MC-38,CT-26cellsConcentration:10,30,100nMIncubationTime:20hResult:ProcessedM2macrophagesupernatantsignificantlyincreasedtheapoptosisrateofMC-38andCT-26cells,withanincreaseofapproximately60%inthe100nMconcentrationgroup.體內研究CSF1R-IN-22(10,20mg/kg;p.o.;oncedailyfor14days)showssignificantantitumoractivityandenhancedcytotoxicT-lymphocyte(CTLs)activityinC57BL/6micebearingsubcutaneousMC-38tumors,withthehigh-dosegroupexhibitingettereffectthanPLX3397(HY-16749)[1].CSF1R-IN-22(20mg/kg;p.o.;oncedailyfor14days)showsstrongeranti-tumoreffectswhencombinedwith100μg/mousePD-1antibody.CXCL9expressionissignificantlypositivelycorrelatedwithsurvival[1].PharmacokineticAnalysisinSDrats[1]RouteDose(mg/kg)AUC0-t(ng·h/mL)t1/2(h)Cl(L/h/kg)Vss(L/kg)Cmax(ng/mL)F(%)i.v.19126.621.340.100.34//p.o.1085939.362.410.12/10867.6594.2AnimalModel:C57BL/6micebearingsubcutaneousMC-38tumors[1]Dosage:5,10,20mg/kgAdministration:p.o.;oncedailyfor14daysResult:Inhibitedtumorgrowth,tumormasswassignificantlylowerthanthatofthecontrolgroup,andinducedapoptosis.Inthehigh-dosegroup,tumorvolumeinhibition(TGI)was65%and30-daysurvivalinmicewas70%.IncreasedmRNAlevelsofM1macrophagemarkers(Nos2,Tnf,Il6,Il1)anddecreasedexpressionofM2macrophagemarkers(Arg1,Chil3l,Rentla,Mrc1).(10mg/kgand20mg/kg)SignificantlyincreasedtheproportionofCD3+CD8+Tcells.Dose-dependentlyreducedtheproportionofimmunosuppressiveTregcellsandmyeloid-derivedsuppressorcells(MDSCs)intumortissues.AnimalModel:C57BL/6micebearingsubcutaneousMC-38tumorsorMC-38-luc[1]Dosage:20mg/kg;100μg/mousePD-1Administration:p.o.;oncedailyfor14daysResult:SignificantlylowertumorbioluminescenceintensityinthecombinationdosegroupthaninthePD-1antibodyaloneorC19alonedosegroupsinbothmodels.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEThecombinationdosegroupsignificantlyincreasedtheproportionofCD3+CD8+TcellsandCTLsinthetumortissuewhilesignificantlydecreasingtheproportionofimmunosuppressiveTregcellsintheMC-38tumormodel.AsignificantincreaseintheinfiltrationofCD8+TcellsandCTLscorrelatedwithasignificantincreaseinthemRNAexpressionofCxcl9.Co-administeredmicehad100%survivalat70days,and70%overcametumorrecurrencewithin91daysafterreinoculationwithMC-38tumorcells.AsignificantreductioninapoptosisandasignificantreductionintheproportionofCD3+CD8+TcellsfollowingtheuseofCXCL9-neutralizingantibody.REFERENCES[1].LvQ,etal.DiscoveryofaNovelCSF-1RInhibitorwithHighlyImprovedPharmacokineticProfilesandSuperiorEfficacyinColorectalCancerImmunotherapy.JMedChem.2024Apr25;67(8):6854-6879.McePdf