Dactolisib-BEZ235-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEDactolisibCat.No.:HY-50673CASNo.:915019-65-7Synonyms:BEZ235;NVP-BEZ235分?式:C??H??N?O分?量:469.54作?靶點(diǎn):PI3K;mTOR;Autophagy作?通路:PI3K/Akt/mTOR;Autophagy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)5%TFA:8.33mg/mL(17.74mM;ultrasonicandwarmingandheatto60°C)DMSO:5mg/mL(10.65mM;ultrasonicandwarmingandheatto60°C)DMF:2mg/mL(4.26mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.1297mL10.6487mL21.2974mL5mM0.4259mL2.1297mL4.2595mL10mM0.2130mL1.0649mL2.1297mL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1/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE、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%1-Methyl-2-pyrrolidinone>>90%PEG300Solubility:≥1.1mg/mL(2.34mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥0.52mg/mL(1.11mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥0.52mg/mL(1.11mM);Clearsolution4.請(qǐng)依序添加每種溶劑：50%PEG300>>50%salineSolubility:12.5mg/mL(26.62mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性Dactolisib(BEZ235)?種具有?服活性的、雙重的pan-classIPI3K和mTOR抑制劑，作?于p110α/γ/δ/β和mTOR，IC50分別為4nM/5nM/7nM/75nM和20.7nM。Dactolisib(BEZ235)抑制mTORC1和mTORC2。IC50&Targetp110αp110βp110δp110γ4nM(IC50)75nM(IC50)7nM(IC50)5nM(IC50)p110α-H1047Rp110α-E545KmTORmTORC14.6nM(IC50)5.7nM(IC50)20.7nM(IC50)mTORC2Autophagy體外研究Dactolisib(BEZ235)potentlyinhibitsPI3KinanATPCompetitiveManner.Dactolisib(BEZ235)(250nM)significantlyreducedthephosphorylationlevelsofthemTORactivatedkinasep70S6K.Dactolisib(BEZ235)alsoleadstoareductionofS235/S236P-RPS6levelswithanIC50of6.5nM,suggestingthatDactolisib(BEZ235)candirectlyinhibitthemTORkinase,asthekinasedomainofmTORishighlyhomologoustotheoneofclassIAPI3K.TheactivityofDactolisib(BEZ235)againstmTORisconfirmedusingabiochemicalmTORK-LISAassay(IC50,20.7nM)[1].TheIC50sofDactolisib(BEZ235)forHCT116,DLD-1,andSW480celllinesare14.3±6.4,9.0±1.5,and12.0±1.6nM,respectively[2].體內(nèi)研究Dactolisib(BEZ235)(45mg/kg,p.o.)treatmentinducescolonictumorregressioninaGEMmodelforsporadicPIK3CAwild-typeCRC[2].Dactolisib(BEZ235)(45mg/kg)isadministeredtoMENXrats(n=2eachgroup)byoralgavageandanimalsaresacrificed1or6hoursaftertreatment.ImmunostainsforP-AKTandP-S6showconsiderablereductionofthetwoproteins,andparticularlyofP-S6,6hoursafteradministrationofDactolisib(BEZ235)whencompareswithPEG-treatedrats.At6hoursaftertreatment,thepituitaryadenomasofDactolisib(BEZ235)-treatedratshasaproteomicprofilesignificantlydifferentfromthetumorsofplacebo-treatedrats[3].PROTOCOLCellAssay[2]HCT116(PIK3CAmutant;kinasedomainatH1047R),DLD-1(PIK3CAmutant;helicaldomainatE545K),2/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEandSW480(PIK3CAwild-type)humanCRCcelllines(ATCC)andisogenicDLD-1PIK3CAmutantandwild-typecellsaremaintainedinDMEM.Cellsareplatedatdifferentinitialdensities(HCT116:3,000cells/well,DLD-1:5,500cells/well,SW480:4,500cells/well,DLD-1PIK3CAmutant:7,000cells/well,andDLD-1PIK3CAwild-type:9,000cells/well)toaccountfordifferentialgrowthkinetics.After16hours,cellsareincubatedwithincreasingconcentrationsofBEZ235(10,100,1000nM),anddrug-containinggrowthmediumischangedevery24hours.Cellviabilityisassessed16hoursaftertheinitialplatingand48hoursafterinitiationofdrugtreatmentusingthecolorimetricMTSassayCellTiter96AQueousOneSolutionCellProliferationAssay.Cellviabilityafterdrugtreatmentisnormalizedtothatofuntreatedcellsalsogrownfor48hours.IC50valuesarecalculatedusing4parameternonlinearregressioninGraphPadPrism5[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[2]Administration[2][3]Tumor-bearingApcCKOmicearerandomlyassignedtotreatmentwitheithercontrolvehiclealone(n=8)or45mg/kgbodyweightBEZ235in10%1-methyl-2-pyrrolidone/90%PEG300(n=8)bydailyoralgavagefor28days.Thetreatmentdoseischosenbasedonliteratureindicatingthat40-50mg/kgbodyweightBEZ235effectivelytreatsmurinetumormodelswithoutadverseeffects.BaseonpharmacokineticstudiesdemonstratingmaximaltissueconcentrationonehourafterNVP-BEZ235administration,tumor-bearingmicearesacrificedonehourafterfinaltreatmentdose.Colonictumorvolumeisassessedusingcalipers(width×length×height)andtumorsareharvestedforbothwesternblotanalysisandimmunohistochemistry.Rats[3]MENX-affectedratsused.ThreedosesofBEZ235aretestedinMENXrats:20,30,and45mg/kg.Asthetwohigherdosescausesaweightloss>10%after10daysoftreatment,thedoseof20mg/kgisusedforfurtherstudies.ForMRIstudies,MENX-affectedratsat7to8monthsofage(withsizeableadenomasbutstillingoodgeneralhealth)aretreatedfor14dayswithBEZ235(20mg/kg)orplacebo(PEG)administereddailyperoralgavage.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?Nature.2018Aug;560(7719):499-503.?CellRes.2019Nov;29(11):895-910.?Blood.2019Oct17;134(16):1323-1336.?SciTranslMed.2018Jul18;10(450).pii:eaaq1093.?NatCommun.2017Jun8;8:15617.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].MairaSM,etal.IdentificationandcharacterizationofNVP-BEZ235,aneworallyavailabledualphosphatidylinositol3-kinase/mammaliantargetofrapamycininhibitorwithpotentinvivoantitumoractivity.