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当前位置： 首页 > 产品中心 > Small_molecule > Medchemexpress/PTC124(Synonyms: Ataluren)/HY-14832/10mM*1mL in DMSO
商品详细Medchemexpress/PTC124(Synonyms: Ataluren)/HY-14832/10mM*1mL in DMSO
Medchemexpress/PTC124(Synonyms: Ataluren)/HY-14832/10mM*1mL in DMSO
Medchemexpress/PTC124(Synonyms: Ataluren)/HY-14832/10mM*1mL in DMSO
商品编号： HY-14832-10mM*1mLinDMSO
品牌： MedChemExp
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产品分类： 小分子
公司分类： Small_molecule
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商品介绍
PTC124targetsnonsensemutations,whichinsertaterminationcodoninthemiddleoftheCFTRgene.

CustomerValidation

  • •Biopolymers.2014Apr;101(4):391-7.
Description

PTC124targetsnonsensemutations,whichinsertaterminationcodoninthemiddleoftheCFTRgene.

IC50&Target

CFTR[1]

InVitro

Thispremature“stop”signal(aclassImutation)preventsthecellfromproducingafull-lengthCFTRprotein[1].PTC124(Ataluren)-anewchemicalentitythatselectivelyinducesribosomalreadthroughofprematurebutnotnormalterminationcodons[2].

InVivo

PTC124(Ataluren)activity,optimizedusingnonsense-containingreporters,promotesdystrophinproductioninprimarymusclecellsfromhumansandmdxmiceexpressingdystrophinnonsensealleles,andrescuesstriatedmusclefunctioninmdxmicewithin2-8 weeksofdrugexposure.PTC124iswelltoleratedinanimalsatplasmaexposuressubstantiallyinexcessofthoserequiredfornonsensesuppression[2].ToinducenonsensesuppressionandincreasePPT1enzymeactivity,theread-throughdrugPTC124(Ataluren)isgivenviaintraperitoneal(i.p.)injectiontomaleCln1R151Xmiceat2monthsofage.Thesetreatmentsareperformedfourtimesdailyfor2consecutivedaysinaproof-of-principlestudy.Usedat10mg/kg,PTC124increasedPPT1enzymeactivity(P=0.0001byunpairedt-test)andproteinlevel(P=0.0014byunpairedt-test)intheliver,butdidnotincreasePPT1enzymeactivityorproteinlevelinthecortex.Thistissue-specificeffectislikelyduetotheinABIlityofPTC124tobreachthebloodbrainbarrier(BBB),whichdecreasedthebioavailabilityofPTC124withinthebrain,andpreventedPTC124fromreachinganefficaciousconcentrationwithinthetherapeuticwindow[3].

ClinicalTrial
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References

  • [1].PettitRS,etal.CFTRModulatorsfortheTreatmentofCysticFibrosis.PT.2014Jul;39(7):500-11.

    [2].WelchEM,etal.PTC124targetsgeneticdisorderscausedbynonsensemutations.Nature,2007,447(7140),87-91.

    [3].MillerJN,etal.ThenovelCln1(R151X)mousemodelofinfantileneuronalceroidlipofuscinosis(INCL)fortestingnonsensesuppressiontherapy.HumMolGenet.2015Jan1;24(1):185-96.

PreparingStockSolutions
ConcentrationVolumeMass1mg5mg10mg
1mM3.5182mL17.5908mL35.1815mL
5mM0.7036mL3.5182mL7.0363mL
10mM0.3518mL1.7591mL3.5182mL
Pleaserefertothesolubilityinformationtoselecttheappropriatesolvent.
CellAssay
[2]

PTC124(Ataluren)ispreparedinDMSOandstored,andthendilutedwithappropriatemedium(DMSO1%)beforeuse[2].

DuplicatesamplesofHEK293cellsharbouringLUC-190(UGA)areincubatedinthepresenceof5 μMPTC124(treated)or1%DMSO(untreated)for20 h.Thecellsarecollected,washedtwiceinphosphatebufferedsaline(PBS),resUSPendedinsamplebuffer(Bio-Rad)andshippedondryicetoKendrickLaboratoriesfortwo-dimensionalelectrophoreticanalysisIsoelectricfocusing(pH 3.5-10)iscarriedoutinglasstubesfor20,000V-hours.One μgofatropomyosininternalstandardisaddedtoeachsample.SeconddimensionSDSslabgelelectrophoresisiscarriedoutforapproximately6 hat25 mApergel.Afterelectrophoresis,gelsaretransferredtoPVDFpaper.ComputerizedanalysisofspotmobilityusedPhoretixsoftware[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

AnimalAdmiNISTration
[3]

PTC124(Ataluren)isdissolvedinPBScontainingDMSOand2-hydroxypropyl-β-cyclodextrin(22%)(Mice)[3].

Mice[3]
Malemicearerandomlyassignedtoeitheratreatmentgrouporvehiclecontrolgroup.Sixtoeightmicepergrouparetreatedwith10or100mg/kgPTC124dissolvedinPBScontainingDMSO(2%for10mg/kgand20%for100mg/kg)and(2-hydroxypropyl)-β-cyclodextrin(22%)viaintraperitoneal(i.p.)injectionsfourtimesdailyfor2consecutivedays.Sixtoeightcontrolmicearetreatedwiththevehicleofthedrug:PBScontainingDMSO(2%or20%)and(2-hydroxypropyl)-β-cyclodextrin(22%).Immediatelyfollowingthelastinjectiononthesecondday,tissuesarecollectedandstoredat−80°Cforfurtheruse.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

References

  • [1].PettitRS,etal.CFTRModulatorsfortheTreatmentofCysticFibrosis.PT.2014Jul;39(7):500-11.

    [2].WelchEM,etal.PTC124targetsgeneticdisorderscausedbynonsensemutations.Nature,2007,447(7140),87-91.

    [3].MillerJN,etal.ThenovelCln1(R151X)mousemodelofinfantileneuronalceroidlipofuscinosis(INCL)fortestingnonsensesuppressiontherapy.HumMolGenet.2015Jan1;24(1):185-96.

MolecularWeight

284.24

Formula

C₁₅H₉FN₂O₃

CASNo.

775304-57-9

Storage
Powder-20°C3years
 4°C2years
Insolvent-80°C6months
 -20°C1month
Shipping

RoomtemperatureincontinentalUS;mayvaryelsewhere

Solvent&Solubility

DMSO:≥52mg/mL

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

Purity:99.88%