LY3009120-DP-4978-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemELY3009120Cat.No.:HY-12558CASNo.:1454682-72-4Synonyms:DP-4978分?式:C??H??FN?O分?量:424.51作?靶點(diǎn):Raf;Autophagy作?通路:MAPK/ERKPathway;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)DMSO:≥38mg/mL(89.51mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.3557mL11.7783mL23.5566mL5mM0.4711mL2.3557mL4.7113mL10mM0.2356mL1.1778mL2.3557mL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)1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE1.請(qǐng)依序添加每種溶劑：5%DMSO>>95%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(5.89mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性LY3009120(DP-4978)泛RAF抑制劑，其抑制BRAFV600E，BRAFWT和CRAFWT的IC50分別為5.8，9.1和15nM。IC50&TargetBRafV600EBrafCRAF5.8nM(IC50)9.1nM(IC50)15nM(IC50)體外研究Inthewhole-cellbasedKiNativassay,LY3009120showsaffinitytoeachRAFisoformwiththeIC50of44,31-47and42nMforARAF,BRAFandCRAFrespectively.LY3009120exhibitsanti-proliferativeeffectsoncelllinesharboringBRAFV600E,KRASG13andKRASG12mutations.LY3009120(1μM)inhibitsthephosphorylationofbothMEK1/2andERK1/2incelllineswithhighbasallevelsofpMEK1/2andpERK1/2(RKOandHCT116)[1].LY3009120showsinhibitoryeffectontumorcellssuchasBxPC-3,NCI-H2405andOV-90celllines.LY3009120(0.01μM)demonstratespotentanddose-dependentinhibitionofphospho-MEKandERKinallthreecelllines.LY3009120demonstratesaconcentration-dependentcellgrowthinhibitionwithIC50valuesof0.04,0.087,and0.007μMagainstH2405,BxPC-3,andOV-90cells,respectively[2].LY3009120inhibitsBRAFWT,CRAFWT,BRAFV600E,andBRAFV600E+G468AwiththeIC50valuesof9.1,15,5.8,and17nM,respectively.LY3009120inducesBRAF-CRAFdimerizationbutinhibitsthephosphorylationofdownstreamMEKandERK.LY3009120alsoinhibitsvariousformsofRAFdimersincludingBRAForCRAFhomodimers[3].LY3009120givesonlyveryminoractivationatverylowdoses,withnearcompleteinhibitionofphospho-ERKatconcentrationsabove100nM[4].體內(nèi)研究LY3009120(20mg/kgbid)displayssignificantactivityininvivoBRAFmutandKRASmutCRCxenograftmodels.InColo205xenografts(BRAFmut),LY3009120resultsinstatisticallysignificanttumorregression,whiletreatmentofHCT116xenografts(KRASmut)resultsinstatisticallysignificantinhibitionoftumorgrowth.LY3009120treatmentreducespMEK1/2inallHT-29xenograftsandreducespERK1/2inthemajorityofHT-29xenografts[1].LY3009120(15or30mg/kg)achievesalmostcompletetumorgrowthregression,andinhibitsdownstreamphospho-MEKandERKbyapproximately70%and60%,respectively,intheH2405model[2].PROTOCOLCellAssay[4]Briefly,cellsaregrowninMcCoy’s5Asupplementedwith10%characterizedfetalbovineserumat37°C,5%CO2,and95%humidity.Cellsareallowedtoexpanduntil75-90%confluencyatwhichpointtheyaresubculturedorharvestedforassayuse.Aserialdilutionoftestcompoundisdispensedintoa384-wellblackclearbottomplateintriplicate.Six-hundred-twenty-fivecellsareaddedperwellin50μLofcompletegrowthmediuminthe384-wellplate.Platesareincubatedfor67hat37°C,5%CO2,and95%humidity.Attheendoftheincubationperiod,10μLofa440μMsolutionofresazurininPBSisaddedtoeachwelloftheplateandplatesareincubatedforanadditional5hat37°C,5%CO2,and95%humidity.Platesarereadona2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESynergy2readerusinganexcitationof540nmandanemissionof600nm.DataareanalyzedusingPrismsoftwaretocalculateIC50values.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalBriefly,5×106to10×106tumorcellsina1:1Matrigelmix(0.2mLtotalvolume)areinjectedsubcutaneouslyAdministration[2]intotherighthindflankoffemaleNIHnuderats.Aftertumorsreachadesiredsizeofapproximately300mm3,animalsarerandomizedintogroupsof8forefficacystudies.Drugs(LY3009120orPLX4032)areadministeredorally(gavage)in0.6-mLvolumeofvehiclewiththedoseschedules.Tumorgrowthandbodyweightaremonitoredovertimetoevaluateefficacyandsignsoftoxicity.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶(hù)使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?CancerRes.2022May18;canres.4152.2021.?CellSyst.2020Nov18;11(5):478-494.e9.?Oncogene.2018Oct;37(43):5719-5734.?CancerSci.2018Jan;109(1):121-131.?Neoplasia.2021Jun5.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].VakanaE,etal.LY3009120,apanRAFinhibitor,hassignificantanti-tumoractivityinBRAFandKRASmutantpreclinicalmodelsofcolorectalcancer.Oncotarget.2017Feb7;8(6):9251-9266[2].ChenSH,etal.OncogenicBRAFDeletionsThatFunctionasHomodimersandAreSensitivetoInhibitionbyRAFDimerInhibitorLY3009120.CancerDiscov.2016Mar;6(3):300-15[3].PengSB,etal.InhibitionofRAFIsoformsand