Niraparib-tosylate-MK-4827-tosylate-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemENiraparibtosylateCat.No.:HY-10619BCASNo.:1038915-73-9Synonyms:MK-4827tosylate分?式:C??H??N?O?S分?量:492.59作?靶點(diǎn):PARP;Apoptosis作?通路:CellCycle/DNADamage;Epigenetics;Apoptosis儲(chǔ)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(shí)驗(yàn)DMSO:100mg/mL(203.01mM;ultrasonicandwarmingandheatto60°C)H2O:1mg/mL(2.03mM;heatto50°C)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.0301mL10.1504mL20.3009mL5mM0.4060mL2.0301mL4.0602mL10mM0.2030mL1.0150mL2.0301mL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(sealedstorage,awayfrommoisture)。-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：1%DMSO>>99%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥0.5mg/mL(1.02mM);Clearsolution2.請(qǐng)依序添加每種溶劑：5%DMSO>>40%PEG300>>5%Tween-80>>50%salineSolubility:≥2.5mg/mL(5.08mM);Clearsolution3.請(qǐng)依序添加每種溶劑：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(5.08mM);ClearsolutionBIOLOGICALACTIVITY?物活性Niraparibtosylate(MK-4827tosylate)?種?效的，具有?物?服利?度的PARP1和PARP2抑制劑，IC50分別為3.8和2.1nM。Niraparibtosylate抑制DNA損傷修復(fù)，誘導(dǎo)凋亡(apoptosis)并具有抗腫瘤活性。IC50&TargetPARP-2PARP-1V-PARPTANK-12.1nM(IC50)3.8nM(IC50)330nM(IC50)570nM(IC50)PARP-31300nM(IC50)體外研究Niraparib(MK-4827)inhibitsPARPactivitywithEC50=4nMandEC90=45nMinawholecellassay.MK-4827inhibitsproliferationofcancercellswithmutantBRCA-1andBRCA-2withCC50inthe10?100nMrange.MK-4827displaysexcellentPARP1and2inhibitionwithIC50=3.8and2.1nM,respectively,andinawholecellassay[1].TovalidatethatNiraparib(MK-4827)inhibitsPARPinthesecelllines,A549andH1299cellsaretreatedwith1μMNiraparib(MK-4827)forvarioustimesandmeasuredPARPenzymaticactivityusingachemiluminescentassay.TheresultsshowthatNiraparib(MK-4827)inhibitsPARPwithin15minutesoftreatmentreachingabout85%inhibitionintheA549cellsat1handabout55%inhibitionat1hfortheH1299cells[2].體內(nèi)研究Niraparib(MK-4827)iswelltoleratedanddemonstratesefficacyasasingleagentinaxenograftmodelofBRCA-1deficientcancer.Niraparib(MK-4827)iswelltoleratedinvivoanddemonstratesefficacyasasingleagentinaxenograftmodelofBRCA-1deficientcancer.Niraparib(MK-4827)ischaracterizedbyacceptablepharmacokineticsinratswithplasmaclearanceof28(mL/min)/kg,veryhighvolumeofdistribution(Vdss=6.9L/kg),longterminalhalf-life(t1/2=3.4h),andexcellentbioavailability,F=65%[1].Niraparib(MK-4827)enhancesradiationresponseofp53mutantCalu-6tumorinbothcases,withthesingledailydoseof50mg/kgbeingmoreeffectivethan25mg/kggiventwicedaily[3].PROTOCOLCellAssay[2]TheinhibitionofPARPisanalyzedinA549andH1299cellsusingtheHTUniversalChemiluminescentPARPAssayKit.Briefly,cellsaretreatedwithDMSOor1μMNiraparib(MK-4827)for15,30,60,or120minutes,trypsinized,andtransferredtoapre-chilledtube.ThecellsarewashedtwicewithicecoldPBSandresuspendedincoldPARPextractionbuffer.Thecellsuspensionsareincubatedonicefor30minuteswithperiodicvortexingtodisruptthecellmembrane.Thesuspensionsarecentrifugedandthesupernatanttransferredtoapre-chilledtubeonice.Thehistonecoatedwellsofthe96-wellplatearerehydratedwith1X2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEPARPbufferandincubatedatroomtemperaturefor30minutes.ThePARPbufferisremovedand20μgofproteinasdeterminedbytheBio-RadProteinAssayisaddedtoeachwellfollowedbydilutedPARP-HSAenzymeand1XPARPbuffer.Thestripwellsarethenincubatedatroomtemperaturefor60minutes,washedtwicewithPBScontaining0.1%TritonX-100,andthenwashedwithPBS.DilutedStrep-HRPisaddedtothestripwellsandincubatedfor60minutesatroomtemperature.Thewellsarewashedagainasbefore.EqualvolumesofPeroxyGlowAandBarecombinedandaddedtothewellsandchemiluminescentreadingsareobtainedimmediatelyusingaplate-reader[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[3]Administration[3]Femalenudemice(NcrNu/Nu)arerandomlyassignedtotreatmentgroupsconsistingof5to8miceeachwhentumorsgrewto6.0mmindiameteratwhichtimetreatmentwithMK-4827isinitiated.MK-4827isgivenatadoseof25mg/kgtwicedailyor50mg/kgoncedailyforeither21daysorisdiscontinuedat9daysfromthetimetumorsreached8mmindiameter.Fractionatedlocaltumorirradiation(XRT)isgivenwhentumorsreach8.0mmindiameter(7.7-8.2mm).Radiation(2Gyperfraction)isdeliveredtothetumor-bearinglegofmiceoncedailyfor14consecutivedaysortwicedailyfor7consecutivedaysusingasmall-animalirradiatorconsistingoftwoparallel-opposed137Cssources,atadoserateof5Gy/min.Duringirradiationun-anesthetizedmicearemechanicallyimmobilizedinajigsothatthetumoriscenteredwithina3.0cmdiameterradiationfieldandtheanimal’sbodyshieldedfromradiationexposure.OnthedaywhenbothMK-4827andradiationaregiven,drugisadministered1hbeforethefirstradiationdoseoftheday.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?CancerCell.2020Dec14;38(6):844-856.e7.?CancerDiscov.2017Sep;7(9):984-998.?JClinInvest.2019Mar1;129(3):1211-1228.?NatCommun.2022Nov19;13(1):7107.?AdvSci(Weinh).2022Oct;9(30):e2201210.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].JonesP,etal.Discoveryof2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide(MK-4827):anoveloralpoly(ADP-ribose)polymerase(PARP)inhibitorefficaciousinBRCA-1and-2mutanttumors.JMedChem.2009Nov26;52(22):7170-85.[2].BridgesKA,etal.Niraparib(MK-4827),anovelpoly(ADP-Ribose)po