Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEGDC-0326Cat.No.:HY-101272CASNo.:1282514-88-8分?式:C??H??N?O?分?量:382.42作?靶點:PI3K作?通路:PI3K/Akt/mTOR儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數據體外實驗DMSO:≥100mg/mL(261.49mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.6149mL13.0746mL26.1493mL5mM0.5230mL2.6149mL5.2299mL10mM0.2615mL1.3075mL2.6149mL請根據產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品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內使?，-20°C儲存時，請在1個?內使?。體內實驗請根據您的實驗動物和給藥?式選擇適當的溶解?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：(為保證實驗結果的可靠性，澄的儲備液可以根據儲存條件，適當保存；體內實驗的?作液，建議您現?現配，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沉淀、析出現象，可以通過加熱和/或超聲的?式助溶)1.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.5mg/mL(6.54mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(6.54mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.54mM);ClearsolutionBIOLOGICALACTIVITY?物活性GDC-0326有效，選擇性的PI3Kα抑制劑，Ki值為0.2nM。IC50&TargetPI3KαPI3KβPI3KδPI3Kγ0.2nM(Ki)26.6nM(Ki)4nM(Ki)10.2nM(Ki)體外研究GDC-0326ishighlyselectiveoverotherkinases.Inapanelof235kinases,onlyoneisinhibitedby>50%byGDC-0326whentestedat1μM.GDC-0326isnotaninhibitorofcytochromeP450enzymestested(IC50>10μMagainst3A4,2C91A2,2C19,2D6),ishighlypermeableinMDCKcellsandhasthermodynamicsolubilityof82μg/mLatpH7.4[1].體內研究GDC-0326ishighlystableinhumanandratlivermicrosomes,andthereisagoodcorrelationwithinvivoratclearance.Itisfoundtohaveconsistentlylowclearanceandhighoralbioavailabilityacrossspeciestested,enablingsignificantsustainedfreedruglevels.DailyadministrationofGDC-0326orallyat0.78,1.56,3.25,6.25,or12.5mg/kgresultsindose-dependentincreaseinTGI(73%,79%,83%,101%,and110%,respectively)andtumorregressions(6PRsoutof10animalat6.25and12.5mg/kg)whencomparedtovehicletreatedmice.DailyadministrationofGDC-0326orallyat0.78,1.56,3.25,6.25,or12.5mg/kgalsoresultsindose-dependentincreaseinTGI(73%,97%,97%,122%,and121%,respectively)intheKPL-4xenograftmodel.Notably,maximumefficacyofGDC-0326isobservedat6.25mg/kgintheKPL-4modelbasedonTGIandtumorregressions(9PRsand1CRoutof10animaltreated)whencomparedtovehicletreatedmice.DosesofGDC-0326upto12.5mg/kgarewelltoleratedbasedonlessthan10%bodyweightloss(datanotshown)[1].PROTOCOLAnimalRats:MaleSprague-Dawleyratsaredosedintravenouslywith1mg/kgofGDC-0326preparedin60%Administration[1]PEG400/10%Ethanol.MaleSprague-DawleyratsaredosedPOwith5mg/kgofGDC-0326in0.5%methylcellulosewith0.2%Tween80(MCT)[1].Mice:FemaleNCRnudemicearedosedintravenouslywith1mg/kgofGDC-0326preparedin60%PEG400/10%EthanolandPOat25mg/kgin0.5%methylcellulosewith0.2%Tween80(MCT)[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].HeffronTP,etal.TheRationalDesignofSelectiveBenzoxazepinInhibitorsoftheα-IsoformofPhosphoinositide3-KinaseCulminating2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEintheIdentificationof(S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yMcePdfHeightCaution:Productha