ONC212-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEONC212Cat.No.:HY-111343CASNo.:1807861-48-8分⼦式:C₂₄H₂₃F₃N₄O分⼦量:440.46作⽤靶点:Apoptosis作⽤通路:Apoptosis储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:50mg/mL(113.52mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.2704mL11.3518mL22.7035mL5mM0.4541mL2.2704mL4.5407mL10mM0.2270mL1.1352mL2.2704mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(5.68mM);Clearsolution1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(5.68mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.68mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性ONC212⼀种氟化的ONC201类似物，⼀种有前景的抗癌剂，也GPR132的选择性激动剂。ONC212还诱导凋亡(apoptosis)[1]。IC50&TargetGPR132[1]体外研究Cellproliferationassayrevealsthatatleastaten-foldlowerconcentrationofONC212isneededtoachieve50%growthinhibitionincomparisontoONC201.ONC212showsGI50valuesintherangeof0.1to0.4μM,whilethecorrespondingONC201GI50valuesareintherangeof4to9μMforthesevenpancreaticcancercelllinestested.Long-termcellproliferationassayshowsthatbothONC201andONC212arecomparableininhibitingcolonyformationata20µMdose.However,ata5µMdose,ONC212isabout50-timesmorepotentthanONC201inpreventingcolonyformationinfouroutofthesevenpancreaticcancercelllinestested.InductionofapoptosisbyONC212isanearliereventthanONC201.TreatmentwithONC201andONC212reducestheexpressionofanti-apoptoticmarkerssuchasXIAPandMCL-1.WesternblotanalysisshowsthatintheHPAF-IIcellline,ATF4andphosphorylatedEIF2αareupregulatedasearlyas6to12hourspostONC201orONC212treatment[2].体内研究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—您⾝边的抑制剂⼤师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