AZD-7762-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEAZD-7762Cat.No.:HY-10992CASNo.:860352-01-8分?式:C??H??FN?O?S分?量:362.42作?靶點(diǎn):CheckpointKinase(Chk)作?通路:CellCycle/DNADamage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:100mg/mL(275.92mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.7592mL13.7961mL27.5923mL5mM0.5518mL2.7592mL5.5185mL10mM0.2759mL1.3796mL2.7592mL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:≥2.5mg/mL(6.90mM);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:≥2.5mg/mL(6.90mM);Clearsolution3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.90mM);Clearsolution4.請(qǐng)依序添加每種溶劑：10%HP-β-CDSolubility:10mg/mL(27.59mM);Clearsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性AZD-7762?種有效的ATP競(jìng)爭(zhēng)性的細(xì)胞周期檢測(cè)點(diǎn)激酶(checkpointkinase，Chk)抑制劑，抑制Chk1的IC50為5nM。IC50&TargetChk1Chk25nM(IC50)5nM(IC50)體外研究AZD-7762(AZD7762)isanequallypotentinhibitorofChk1andChk2invitro.AZD-7762potentlyinhibitsChk1andChk2,abrogatesDNAdamage-inducedSandG2checkpoints,enhancestheefficacyofNSC613327andSKF104864A,andmodulatesdownstreamcheckpointpathwayproteins.AZD-7762potentlyinhibitsChk1phosphorylationofacdc25CpeptidewithanIC50of5nMasmeasuredbyascintillationproximityassay.TheKiforAZD-7762isdeterminedtobe3.6nM.KineticcharacterizationsuggeststhatAZD-7762bindsintheATP-bindingsiteofChk1andisthoughttocompetedirectlyforATPbindinginareversiblemanner.AZD-7762isshowntoabrogatetheG2arrestinducedbyCamptothecinwithanaverageEC50of10nM(n=12)andmaximalabrogationintherangeof100nM[1].體內(nèi)研究IntheratH460-DNp53xenograftstudy,AZD-7762(AZD7762)potentiatestheantitumoractivityofNSC613327inadose-dependentmannerbyadecreasein%T/Cwithincreasingdose(48%and32%,10and20mg/kgAZD-7762,respectively).InthemousexenograftstudyincombinationwithCPT-11,SW620establishedtumorsaretreatedwithvehicle,CPT-11alone,AZD-7762alone,orAZD-7762incombinationwithCPT-11.AZD-7762dosedaloneshowsinsignificantantitumoractivity,whereasCPT-11alonedisplaysstrikingandsignificantactivity(%T/Cwithincreasingdoseis9and1,respectively).IncombinationwithAZD-7762,%T/Cincreasessignificantlyto-66%and-67%,respectively[1].AZD7762combinationwithCX-5461inducescancercelldeathofTp53-null(Tp53-/-)Eμ-Myclymphomacellsinvitroandinvivo[2].PROTOCOLCellAssay[1]SW620(5.5×103perwell)orMDA-MB-231(5×103perwell)cellsareseededin96-wellplatesandincubatedovernight.Cellsaredosedfor24hwitha9-pointtitrationofNSC613327rangingfrom0.01to100nMwithorwithoutaconstantdoseofAZD-7762(300nM).Controlwellsaredosedwithvehiclealone(0.1%DMSO)or300nMAZD-7762.After24h,mediumisremovedandAZD-7762aloneisaddedbacktothewellstreatedpreviouslywithAZD-7762foranadditional24h.Cellsarethenincubatedindrug-freemediumforanadditional72h.TheeffectoncellproliferationisdeterminedbyMTSassay[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAnimalMiceandRats[1]Administration[1][2]MaleNCrmiceandmalernuratsareused.Forxenograftmodelsinmice,tumorcellsareharvested,pelletedbycentrifugationfor5min,andresuspendedinsterilePBS.Cells(3×103-6×106)otherightflankofthemiceinavolumeof0.1to0.2mLusinga25-gaugeneedle.Tumorsareallowedtogrowtothedesignatedsizeof100to200mm3beforetheadministrationofcompound.Forxenograftmodelsinrats,Cellsareharvested,pelletedbycentrifugationfor5min,andresuspendedin50%sterilePBSand50%Matrigel.Ratsreceivea5Gywhole-bodyradiationdose5daysbeforecellimplantationtoimprovetumorgrowth.H460-DNp53cells(1×107)areimplanteds.c.,intotherightflankoftheratsinavolumeof0.2mLusinga25-gaugeneedle.Tumorsareallowedtogrowtothedesignatedsizeof100to200mm3beforetheadministrationofAZD-7762.AZD-7762(10and20mg/kg)isadministeredbyi.v.injectionviathetailvein.Cyclicschedulesareusedandtreatmentrangedfromthreetofivecycles.Eachcycleincludesadministrationofastandardagent(NSC613327orCPT-11)every3daysfollowbydeliveryofAZD-7762.Tumorvolumesaremeasuredwithelectroniccalipersandcalculated.Mice[2]C57Bl/6miceareintravenouslyinjectedwith2×105Eμ-MycB-lymphomacellsinPBSandtreatedwithpharmacologicalinhibitorsfrom8dayspost-injection.Treatmentofmiceiscontinueduntilanethicalend-pointisreached;hunchedposture,ruffledfur,enlargedlymphnodes,labouredbreathing,weightlossgreaterthan20%ofstartbodyweightandlimitedmobilityorparalysis.AZD7762isdeliveredintraperitoneallyin10.3%-hydroxypropyl-β-cyclodextrinin0.9%salineat20mg/kgdailyonweekdays.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?NatNanotechnol.2021Jul;16(7):830-839.?CellMetab.2022Feb7;34(3):424-440.e7.?SciTranslMed.2021Jan20;13(577):eaba7401.?SciTranslMed.2018Jul18;10(450).pii:eaaq1093.?ActaPharmacolSin.20