Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEMELK-8ahydrochlorideCat.No.:HY-100368ACASNo.:2096992-20-8Synonyms:NVS-MELK8ahydrochloride分?式:C??H??ClN?O分?量:469.02作?靶點:MELK作?通路:PI3K/Akt/mTOR儲存?式:4°C,sealedstorage,awayfrommoisture*Insolvent:-80°C,6months;-20°C,1month(sealed

storage,awayfrommoisture)溶解性數(shù)據(jù)體外實驗H2O:≥100mg/mL(213.21mM)DMSO:8.6mg/mL(18.34mM;Needultrasonicandwarming)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.1321mL10.6605mL21.3211mL5mM0.4264mL2.1321mL4.2642mL10mM0.2132mL1.0661mL2.1321mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month(sealedstorage,awayfrommoisture)。-80°C儲存時，請在6個?內(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結(jié)果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)配，當天使?；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?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE1.請依序添加每種溶劑：PBSSolubility:50mg/mL(106.61mM);Clearsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性MELK-8ahydrochloride?種新穎的母體胚胎亮氨酸拉鏈激酶（MELK）抑制劑，其IC50值為2nM。IC50&TargetIC50:2nM(MELK)[1]體外研究MELK-8aremainsverypotent(IC50=140nM)whentheATPconcentrationinthebiochemicalassayisshiftedfrom20μMto2mM.Itspotencyiswelltrackedbetweenfull-lengthMELKversuscatalyticdomainconstruct(5nMversus2nM).Itonlyinhibitssevenoff-targetkinasesinadditiontoMELKwith>85%inhibitionofbindingat1μMdemonstratinggreatselectivity.Thecompoundisatleast90-foldmoreselectiveintargetingMELKinallcases.MELK-8aisfairlysoluble(0.22g/LatpH6.8)andshowsagoodpermeabilityintheCaco-2assay.MELK-8ainhibitsthegrowthofMDA-MB-468cellsandMCF-7cellswithanIC50ofapproximately0.06and1.2μM,respectively[1].體內(nèi)研究SubcutaneousadministrationofMELK-8aat30mg/kginC57BL/6miceresultsingoodplasmaexposure.Thecompoundadsorptionintothesystemiccirculationisrapid(Tmax=0.4h)andpeakplasmaconcentrationreaches6.6μM.AnascendingdosePKstudyinfemaleathymicnudemiceshowsthattherateofcompoundreleaseismaximalat120mg/kgandallclearancemechanismscanbesaturatedat240mg/kg.However,whenadministeredorallyat10mg/kginC57BL/6malemice,itshowsverypoorPK(3.6%oralbioavailability)consistentwithveryhighinvivoclearance[1].PROTOCOLCellAssay[1]MDA-MB-468andMCF7cellsareseededingrowthmediuminto96-wellplatesat1000and4000cells/well,respectively.Sixteenhoursafterplating,MELK-8aareaddedandincubatedfor7days.Foreachwell,ATPLitereagentisaddedandincubated.Luminescenceismeasuredonanmultilabelplatereader[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice:Forpharmacokineticstudies,theintravenousandoraldoseispreparedinasolutioncontaining5%Administration[1]ethanol,100%PG,5%CremophorEL,and80%PBS.Thesubcutaneousdoseisformulatedin10%PGand25%(20%,v/v)Solutol.Plasmasamplesarecollectedatspecifiedtimepointsandstoredfrozen(?20°C)untilMELK-8aanalysis.AnLC?MS/MSmethodisusedtoquantitateMELK-8adruglevelsinplasma[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻?CellRep.2017Dec5;21(10):2829-2841.?JBiolChem.2020Feb21;295(8):2359-2374.?SchoolofMedicine,DepartmentofPharmacology.2020Jun.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESeemorecustomervalidationsonwww.MedChemEREFERENCES[1].TouréBB,etal.TowardtheValidationofMaternalEmbryonicLeucineZipperKinase:Discovery,OptimizationofHighlyPotentandSelectiveInhibitors,andPreliminaryBiologyInsight.JMedChem.2016May26;59(10):4711-23.McePdfHeight