Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEFLT3-IN-3Cat.No.:HY-112145CASNo.:2229050-90-0分?式:C??H??N?O分?量:490.64作?靶點(diǎn):FLT3作?通路:ProteinTyrosineKinase/RTK儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:250mg/mL(509.54mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.0382mL10.1908mL20.3815mL5mM0.4076mL2.0382mL4.0763mL10mM0.2038mL1.0191mL2.0382mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.08mg/mL(4.24mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.08mg/mL(4.24mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.08mg/mL(4.24mM);ClearsolutionBIOLOGICALACTIVITY?物活性FLT3-IN-3?種有效的FLT3抑制劑，抑制FLT3WT和FLT3D835Y，IC50分別為13和8nM。IC50&TargetIC50:13nM(FLT3WT),8nM(FLT3D835Y)[1]體外研究FLT3-IN-3(Compound7d)inhibitstheproliferationofFLT3-ITDpositiveMV4-11andMOLM-13celllinesveryeffectivelyatlownanomolarconcentrations(GI50values2and1nM,respectively)[1].FLT3-IN-3(1nM,10nM,100nM,1μMand10μM;72hours)inhibitstheBa/F3FLT3-ITDcellswiththeGI50of0.034±0.015μM,andinhibitstheparentalBa/F3cellswiththeGI50valueof1.136±0.389μM[1].Concentrationsaslowas1nMaresufficienttoblocktheautophosphorylationoftheFLT3receptortyrosinekinaseatthreedifferenttyrosineresidues(589,591,and842).Moreover,thisinhibitionsuppressesphosphorylationofseveraldownstreamtargetsofFLT3.Notably,FLT3-IN-3(0.01,0.1,1,10and100nM;1hours)abolishesphosphorylationofSTAT5atY694,whichisadirectsubstrateoftheoncogenicFLT3-ITDvariant.ThesecondpathwayaffectedistheMAPKcascade:Twokeycomponentsofthissignalingpathway,ERK1/2(T202/Y204)andMEK1/2(S217/221),exhibitreducedphosphorylationupontreatmentwithFLT3-IN-3.FLT3-IN-3alsointerferswithPI3K/AKTpathwaywhichisconfirmedbyreducedphosphorylationofAKTatS473[1].CellProliferationAssay[1]CellLine:MurineBa/F3FLT3-ITDandparentalBa/F3cellsConcentration:1nM,10nM,100nM,1μMand10μMIncubationTime:72hoursResult:TheGI50sforBa/F3FLT3-ITDcellsandparentalBa/F3cellsare0.034±0.015μMand1.136±0.389μM,respectively.WesternBlotAnalysis[1]CellLine:MV4-11cellsConcentration:0.01,0.1,1,10and100nMIncubationTime:1hoursResult:Concentrationsaslowas1nMweresufficienttoblocktheautophosphorylationoftheFLT3receptortyrosinekinaseatthreedifferenttyrosineresidues(589,591,and842).2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE體內(nèi)研究AsingledoseofFLT3-IN-3(Compound7d;10mg/kg;i.p.)inmicewithsubcutaneousMV4-11xenograftscausessustainedinhibitionofFLT3andSTAT5phosphorylationover48hours[1].AnimalModel:Femaleathymicnu/numicewithsubcutaneouslyimplantedMV4-11xenografts[1]Dosage:10mg/kgAdministration:Intraperitoneal(i.p.)injection;48hoursResult:EffectivelyinhibitedFLT3-ITDautophosphorylationinMV4-11xenografts.REFERENCES[1].GuckyT,etal.DiscoveryofN2-(4-Amino-cyclohexyl)-9-cyclopentyl-N6-(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2,6-diamineasaPotentFLT3KinaseInhibitorforAcuteMyeloidLeukemiawithFLT3Mutations.JMedChem.2018May10;61(9):3855-3869.McePdfHeightCaution:P