Voxtalisib-XL765-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEVoxtalisibCat.No.:HY-15900CASNo.:934493-76-2Synonyms:XL765;SAR245409分?式:C??H??N?O分?量:270.29作?靶點(diǎn):PI3K;mTOR作?通路:PI3K/Akt/mTOR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:10mg/mL(37.00mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM3.6997mL18.4986mL36.9973mL5mM0.7399mL3.6997mL7.3995mL10mM0.3700mL1.8499mL3.6997mL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.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥1mg/mL(3.70mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥1mg/mL(3.70mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥1mg/mL(3.70mM);ClearsolutionBIOLOGICALACTIVITY?物活性Voxtalisib(XL765)?種有效的PI3K抑制劑，抑制p110α，p110β，p110γ和p110δ，IC50分別為39,113,9和43nM，也抑制DNA-PK(IC50=150nM)和mTOR(IC50=157nM)。Voxtalisib(XL765)抑制mTORC1和mTORC2，IC50s分別為160和910nM。IC50&Targetp110γp110αp110δp110β9nM(IC50)39nM(IC50)43nM(IC50)113nM(IC50)mTORmTORC1mTORC2DNA-PK157nM(IC50)160nM(IC50)910nM(IC50)150nM(IC50)體外研究Voxtalisib(XL765)displayspotentinhibitoryactivityagainstclassIPI3Kisoformsp110α,p110β,p110δ,andp120γ,withIC50sof39,110,43,and9nM,respectively.TheIC50valueforinhibitionofPI3KαbyVoxtalisibisdeterminedatvariousconcentrationsofATP,revealingVoxtalisibbeanATP-competitiveinhibitorwithanequilibriuminhibitionconstant(Ki)valueof13nM.VoxtalisibalsoinhibitsmTOR(IC50sof160and910nMformTORC1andmTORC2,respectively)inanimmune-complexkinaseassayandthePI3K-relatedkinaseDNA-PK(IC50valueof150nM).Incontrast,Voxtalisib(XL765)hasrelativelyweakinhibitoryactivitytowardtheclassIIIPI3Kvacuolarsortingprotein34(VPS34;IC50valueof~9.1μM).ConsistentwithitsinhibitoryactivityagainstpurifiedPI3Kproteins,SAR245409inhibitsEGF-inducedPIP3productioninPC-3andMCF7cellswithIC50sof290and170nM,respectively.TheabilityofVoxtalisibtoinhibitphosphorylationofkeysignalingproteinsdownstreamofPI3KisexaminedbyassessingitseffectsonEGF-stimulatedphosphorylationofAKTandonnonstimulatedphosphorylationofS6inPC-3cellsbycell-basedELISA.VoxtalisibinhibitstheseactivitieswithIC50sof250and120nM,respectively.InMCF7andPC-3cells,Voxtalisibinhibitsproliferation(monitoredbyBrdUrdincorporation)withIC50sof1,070and1,840nM,respectively.TofurthercharacterizetheeffectsofVoxtalisibontumorcellgrowth,anassaymonitoringtheanchorage-independentgrowthofPC-3andMCF7cellsinsoftagarovera14-dayperiodisused.SAR245409inhibitscolonygrowthwithanIC50valueof270nMinPC-3cellsand230nMinMCF7cells[2].體內(nèi)研究OraladministrationofVoxtalisib(XL765)causesadose-dependentdecreaseofphosphorylationofAKT,p70S6K,andS6inthetumors,reachingamaximumof84%inhibitionofS6phosphorylationat30mg/kgat4hours.Thedose-responserelationshipsderivefromthe4hourstimepointpredict50%inhibitionofAKT,p70S6K,andS6phosphorylationtooccuratdosesof19mg/kg(pAKTT308andpAKTS473),51mg/kg(p-p70S6K),and18mg/kg(pS6).InhibitionofAKT,p70S6K,andS6phosphorylationinMCF7tumorsfollowinga30mg/kgdoseofVoxtalisibismaximalat4hours,reaching61%to84%;however,thelevelofinhibitiondecreasesto0%to42%by24hours,andminimalornoinhibitionisevidentby48hours.Followinga100mg/kgdoseofVoxtalisib,inhibitionisalsomaximalat4hours(52%-75%)[2].2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEPROTOCOLCellAssay[2]CellularproliferationisassessedusingtheCellProliferationELISA,BromodeoxyuridineChemiluminescenceKit.CytotoxicityisassessedusingtheATPBioluminescenceAssayasfollows:PC-3,MCF7,A549,LS174T,MDA-MB-468,U87-MG,andOVCAR-3cellsareplatedatdensitiesof7×103,1.5×104,6×103,7×103,7×103,6×103,1.5×104cellsperwell,respectively,onto96-wellmicrotiterplatesinculturemedium,incubatedat37°C,5%CO2for18hours,andthentreatedwithaserialdilutionofcompoundinmediumcontainingafinalconcentrationof0.3%DMSO.Triplicatewellsareusedforeachcompoundconcentration.Controlwellsreceive0.3%DMSOinmedia.Culturesareincubatedat37°C,5%CO2foranadditional24hoursandcellsarethenassayedforviabilityusingtheViaLightHSKit[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[2]Administration[2]Invivoefficacystudiesareperformedinathymicnudemice.TumorcellsareculturedinDMEMsupplementedwith10%FBS(20%forPC-3andOVCAR-3cells),Penicillin-Streptomycin,andnonessentialaminoacidsat37°Cinahumidified5%CO2atmosphere.Onday0,cellsareharvestedbybrieftrypsinization,and1to5×106cellsin0.1mLice-coldHanksBalancedSaltSolutionareimplantedsubcutaneously(OVCAR-3)orintradermally(MCF7andU-87MG)intothehindflankoffemaleathymicnudemice.InthecaseoftheMCF7model,anestrogenpellet(IRA)isimplantedsubcutaneouslyatthenapeofneckatthetimeoftumorcellimplantation.Atotalof3×106PC-3cellsaresimilarlyharvestedandimplantedsubcutaneouslyintothehind-flankof5-to8-week-oldmalenudemice.Tumorgrowthismonitoredweeklywithcalipersuntilstaginganddoseinitiation.Duringthedosingperiod,bodyandtumorweightsareassessed.Voxtalisib(XL-765)isformulatedinsterilewater/10mMHClorwaterandadministeredattheindicateddosesandregimensbyoralgavageatadosevolumeof10mL/kg.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?SciTranslMed.2018Jul18;10(450).pii:eaaq1093.?ActaNeuropathol.2019Sep;138(3):443-456.?FrontPharmacol.2020Nov11;11:580407.?Molecules.2020Apr23;