Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEONC212Cat.No.:HY-111343CASNo.:1807861-48-8分?式:C??H??F?N?O分?量:440.46作?靶點:Apoptosis作?通路:Apoptosis儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數據體外實驗DMSO:50mg/mL(113.52mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.2704mL11.3518mL22.7035mL5mM0.4541mL2.2704mL4.5407mL10mM0.2270mL1.1352mL2.2704mL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%salineSolubility:≥2.5mg/mL(5.68mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(5.68mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.68mM);ClearsolutionBIOLOGICALACTIVITY?物活性ONC212?種氟化的ONC201類似物，?種有前景的抗癌劑，也GPR132的選擇性激動劑。ONC212還誘導凋亡(apoptosis)[1]。IC50&TargetGPR132[1]體外研究Cellproliferationassayrevealsthatatleastaten-foldlowerconcentrationofONC212isneededtoachieve50%growthinhibitionincomparisontoONC201.ONC212showsGI50valuesintherangeof0.1to0.4μM,whilethecorrespondingONC201GI50valuesareintherangeof4to9μMforthesevenpancreaticcancercelllinestested.Long-termcellproliferationassayshowsthatbothONC201andONC212arecomparableininhibitingcolonyformationata20μMdose.However,ata5μMdose,ONC212isabout50-timesmorepotentthanONC201inpreventingcolonyformationinfouroutofthesevenpancreaticcancercelllinestested.InductionofapoptosisbyONC212isanearliereventthanONC201.TreatmentwithONC201andONC212reducestheexpressionofanti-apoptoticmarkerssuchasXIAPandMCL-1.WesternblotanalysisshowsthatintheHPAF-IIcellline,ATF4andphosphorylatedEIF2αareupregulatedasearlyas6to12hourspostONC201orONC212treatment[2].體內研究Biweeklyoraladministrationof50mg/kgONC212markedlyinhibitsAcutemyeloidleukemia(AML)expansionandprolongsoverallsurvival(p=0.0003).Mediansurvivalincreasesfrom43dincontrolsto49dintheONC212-treatedgroup(+14%)[1].ONC212treatmentexhibitssignificantlygreatergrowthinhibitionincomparisontoONC201.Adoseof50mg/kgofONC212administeredthree-timesaweekissufficienttoleadtosignificantgrowthinhibitionoftumorscomparetothecontrolgroupforthesetwomodels.ResultsdemonstratethatONC212treatedtumorsshowreducedproliferationintheHPAF-IImodel[2].InvivotoxicityassessmentexperimentsshowthatONC212iswelltoleratedupto250mg/kg.300mg/kgofONC212causessplenicdamageandelevatesliverenzymes.ONC212hasaslightlyshorterhalf-lifethanONC201,withaclearancefromthebloodat12hours,T1/2of4.3hours,andCmaxof1.4μg/mL[3].PROTOCOLCellAssay[2]AllpancreaticcancercelllinesaretreatedwithONC201orONC212attheindicateddosesandtime-points.Post-treatment,bothfloatingandadherentcellsarecollected,fixedin70%ethanolandstainedwithpropidiumiodideinthepresenceofribonucleaseA.Flowcytometricdataiscollectedusingaflowcytometer.Thesub-G1fraction(apoptotic)isquantified,andanalysisisperformedtoquantifythedistributionofcellsinG1,SandG2-Mphasesofthecellcycleutilizing[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAnimalSix-toseven-week-oldfemaleathymicnu/numiceareusedinthisstudy.Atotalof3to5×106luciferase-Administration[2]expressingcellsaresuspendedin50μLofPBSmixedwith50μLofMatrigelandsubcutaneouslyinjectedintotherearflanksofthemice.Whentumorvolumereachesanaverageof100to150cm3,micearerandomlyassignedtotheindicatedcontrolortreatmentgroups.ONC201andONC212aredeliveredinasolutionof10%DMSO,20%Kolliphor?ELand70%PBSbyoralgavage.Thelength(L)andwidth(W)ofthetumorsaremeasured1to2timesaweekusingadigitalcaliper,andthevolumeofthetumoriscalculated.Micearealsoweighedonceaweektomonitorsignsofdrugtoxicity[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].TakenobuNii,etal.TheNovelImipridoneONC212InducesPronouncedAnti-LeukemiaEffectsinVitroandInVivoandIsHighlySynergisticwiththeBCL-2InhibitorABT-199.ASH.2017.[2].LevA,etal.Anti-pancreaticcanceractivityofONC212involvestheunfoldedproteinresponse(UPR)andisreducedbyIGF1-RandGRP78/BIP.Oncotarget.2017Sep12;8(47):81776-81793.[3].WagnerJ,etal.Preclinicalevaluationoftheimipridonefamily,analogsofclinicalstageanti-cancersmallmoleculeONC201,revealspotentanti-cancereffects