IHMT-TRK-284-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEIHMT-TRK-284Cat.No.:HY-146697CASNo.:2416844-79-4分?式:C??H??N?OS分?量:473.59作?靶點(diǎn):TrkReceptor;c-Fms;PDGFR;Bcr-Abl;c-Kit;Apoptosis作?通路:NeuronalSignaling;ProteinTyrosineKinase/RTK;Apoptosis儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物IHMT-TRK-284(Compound34)?種有效的、具有?服活性的typeIITRKkinase抑制劑，對(duì)TRKA,B,C的IC50值分別為10.5,0.7和2.6活性體內(nèi)抗腫瘤效果[1]。IC50&TrkBTrkCTrkATarget0.7nM(IC50)2.6nM(IC50)10.5nM(IC50)PDGFRαPDGFRβAbl124.2nM(IC50)95.7nM(IC50)83.6nM(IC50)體外IHMT-TRK-284(Compound34)(0-10μM,72h)showsantiproliferativeeffectsagainstBaF3cells,apanelofkinasetransformedBaF3ce研究IHMT-TRK-284(0-10μM,24h)inducesapoptosisandarreststhecellcycleintoG0/G1phaseinKM-12-LUCcells[1].IHMT-TRK-284exertsitsinhibitoryeffecttothecoloncancercellsthroughon-targetinhibitionofTRK[1].IHMT-TRK-284couldovercomedrugresistantmutantsincludingV573MandF589LintheATPbindingpocketaswellasG667C/SintheIHMT-TRK-284showsselectivityoverVEGFR2kinase[1].CellProliferationAssay[1]CellLine:BaF3cells,apanelofkinasetransformedBaF3cells,andKM-12-LUCcellsConcentration:0-10μMIncubationTime:72hResult:ShowedantiproliferativeeffectsagainstBaF3cells,apanelofkinasetransformedBaF3cells,andKM-12-LUCcells.1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAntiproliferativeeffectsofIHMT-TRK-284againstapanelofkinasetransformedBaF3cells[1].TargetBaF3-TEL-ABLBaF3-TEL-CSF1RBaF3-TEL-KITBaF3-TEL-PDGFRαBaF3-TEL-PDGFRβBaF3-TEL-TRKA(nM)411.149AntiproliferativeeffectsofIHMT-TRK-284againstapanelofTRKswt/mutantstransformedBaF3cells(n=3)[1].ShowedantiproliferativeeffectswithGI50sof1.4±0.011,0.007±0.001,0.003±0.001,0.004±0.001,0.194±0.013TRKA,BaF3-LMNA-TRKA-V573M,BaF3-LMNA-TRKA-F589L,BaF3-LMNA-TRKA-G595R,BaF3-LMNA-TRKA-G667WesternBlotAnalysis[1]CellLine:BaF3-TEL-TRKA,BaF3-TEL-TRKB,BaF3-TEL-TRKC,BaF3-LMNATRKA-V573M,BaF3-LMNA-TRKA-F589L,BaF3-cellsConcentration:0,0.01,0,03,0.1,0.3,1,3,and10μMIncubationTime:2hResult:IntransformedBaF3cells:InhibitedthephosphorylationofTRKAY490(EC50=0.026μM)andcorrespondingtyrosin=0.029μM);potentlyinhibitedthephosphorylationofY490inV573M,F589L,andG667C/SmutantswithEC50sof0LUCcells:BlockedthephosphorylationofTRKAY490attheconcentrationof0.01μM;remarkablyinhibitedthephosERK1/2(T202/Y204)(EC50lessthan0.03μM).ApoptosisAnalysis[1]CellLine:KM-12-LUCcellsConcentration:0,0.01,0,03,0.1,0.3,1,3,and10μMIncubationTime:24hResult:Induceddose-dependentcellapoptoticdeath.CellCycleAnalysis[1]CellLine:KM-12-LUCcellsConcentration:0,0.01,0,03,0.1,0.3,1,3,and10μMIncubationTime:24hResult:ArrestedthecellcycleintoG0/G1phase.體內(nèi)研IHMT-TRK-284(Compound34)(40and80mg/kg;p.o.;daily,10days)showsgoodinvivoPKandantitumorefficacyproperties[1].究AnimalModel:Four-weekoldfemalenu/numice,onemillionBaF3-TELTRKA,BaF3-TEL-TRKB,BaF3-TEL-TRKC,BaF3-LMNA-TRcellsinDMEMmediumwereformulatedasa1:1mixturewithmatrigelandinjectedintothesubcutaneousspaceontDosage:40mg/kgand80mg/kg2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAdministration:Dailyoralgavage,10daysResult:Dose-dependentlyinhibitedtheBaF3-TEL-TRKA,BaF3-TEL-TRKB,andBaF3-TEL-TRKCtumorprogressionwithTGinhibitedthetumorprogressionandexhibitedtheTGIof93%at40mg/kg/dayand95%at80mg/kg/dayinKM-12-LUtumorgrowthwithTGIvaluesof88%and89%respectivelyat80mg/kgdosageinBaF3-LMNA-TRKA-F589LandBaAnimalModel:Mice,spraguedawleyrats,andbeagledogs[1]Dosage:1mg/kgand10mg/kgAdministration:Intravenousinjectionandoraladministration(PharmacokineticAnalysis)Result:PharmacokineticstudyofIHMT-TRK-284inmice,spragueREFERENCESdawleyrats,andbeagledogsa[1][1].BeileiWang,etal.Discoveryof(E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-ParameterMiceyl)acetamide(IHMT-TRK-284)asanovelorallyavailabletypeIITRKkinaseini.v.(1mg/kg)MiceJMedChem.2020Dec1;207:112744.p.o.(10mg/kg)RatsMcePdfHeighti.v.(1mg/kg)Ratsp.o.(10mg/kg)BeagleDogsi.v.(1mg/kg)BeagleDogsp.o.(10mg/kg)AUC(0-t)(ng/mL*h)7481431393952323464Tmax(h)0.0331.50.034.70.084.3T1/2(h)2.50.0