Ataluren (PTC124)

Catalog No.S6003

Ataluren (PTC124) selectively induces ribosomal read-through of premature but not normal termination codons, with EC50 of 0.1 μM in HEK293 cells, may provide treatment for genetic disorders caused by nonsense mutations (e.g. CF caused by CFTR nonsense mutation). Phase 3.

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Ataluren (PTC124) Chemical Structure

Ataluren (PTC124) Chemical Structure
Molecular Weight: 284.24

Validation & Quality Control

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  • Ataluren (PTC124) Mechanism

Product Description

Biological Activity

Description Ataluren (PTC124) selectively induces ribosomal read-through of premature but not normal termination codons, with EC50 of 0.1 μM in HEK293 cells, may provide treatment for genetic disorders caused by nonsense mutations (e.g. CF caused by CFTR nonsense mutation). Phase 3.
Targets CFTR [1]
(HEK293 cells)
In vitro Compared with Gentamicin which is only active at much higher concentrations, PTC124 is a more potent nonsense-suppressing agent and exhibits 4- to 15-fold stimulation of read-through relative to controls. PTC124 (0.01-3 μM) promotes dose-dependent read-through of all three nonsense codons in HEK293 cells harboring LUC-190 nonsense alleles with the highest read-through at UGA, followed by UAG and then UAA, but it does not suppress multiple proximal nonsense codons. Like Gentamicin, PTC124 is most active when a pyrimidine (in particular cytosine, C) follows the nonsense codon. Consistent with the stable cell line reporter assay, PTC124 (17 μM) promotes significant production of dystrophin in primary muscle cells from Duchenne muscular dystrophy (DMD) patients or MDXMDX mice expressing dystrophin nonsense alleles. PTC124 selectively promotes ribosomal read-through of premature termination but not normal termination codons, even at concentrations substantially greater than the values achieving maximal activity. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
BAC_MMA∗EGFPMVzGeY5kfGmxbjDBd5NigQ>?NYTzfos4OjEEoN88US=>MlLKO|LDqGkEoB?=NXPONnVqTE2VTx?=NY\lSo0yemW|dXz0d{BqdiCjIIPp[45q\mmlYX70JIlv[3KnYYPlJIlvKG2nZHnhckBx\WGtIH\seY9z\XOlZX7j[S=>MnvKNlMxPDFzOEm=
Mut−/−MUTStop+/−NIDZS5RHfW6ldHnvckBCe3OjeR?=M3PvfFIxyqEQvF2=Mn;CO|LDqGkEoB?=NFrudnFFVVORNUfX[W5jcW6lcnXhd4V{KHSqZTDhcY92dnRib3dCpG1WXMLibWLORS=>NX;4NpJOOjNyNEGxPFk>
HEK293TNV:3d5gxTnWwY4Tpc44hSXO|YYm=NVHCepIzOTBiwsXnM41tM1zvemROW09?MkTYdoV{fG:{ZYOg[pVtdC2uZX7neIghcGG{bX;ubY4h[TFiKPMIwFgxKGuGYTmgbY4heC6UM{HYMZRz[W6|ZnXjeIVlKGOnbHzzM4\ZTFI{ODJ5NkSw
ML1NGX3[WtHfW6ldHnvckBCe3OjeR?=NWK1bIFIOy5|L{GwxsDPxE1?M3LyZlQ5KGh?NE\0epVFVVORMkL5bY5kemWjc3XzJGFTW0JiYXP0bZZqfHl?NV7Kb2JWOjJ7N{G5OVk>
ML2NGDPNWRHfW6ldHnvckBCe3OjeR?=Mn;EN{4{NzFywrFOwG0>NILkdGI1QCCqNFy2RVBFVVORMmHYbY5kemWjc3XzJGFTW0JiYXP0bZZqfHl?Ml3kNlI6PzF7NUm=

... Click to View More Cell Line Experimental Data

In vivo Due to functional recovery of dystrophin production, oral, intraperitoneal or combined dosing of PTC124 for 2-8 weeks partially rescues functional strength deficit in dystrophic muscles of MDX mice, and results in partial protection against contraction-induced injury in the extensor digitorum longus (EDL) muscles, as well as significant reductions in serum creatine kinase values. [1] In Cftr-/- mice expressing a human CFTR-G542X transgene, subcutaneous or oral administration of PTC124 (~60 mg/kg) suppresses the G542X nonsense mutation in a dose-dependent manner, leading to a significant restoration of human (h)CFTR protein expression and function without any effect on nonsense-mediated mRNA decay (NMD) or other aspects of mRNA stability. PTC124 treatment (60 mg/kg) restores 29% of the normal intestinal transepithelial cAMP-stimulated shortcircuit currents observed in Cftr+/+ mice, displaying a significant advantage compared with Gentamicin. [2]
Features Demonstrates oral bioavailability, and an appropriate safety toxicology profile.

Protocol(Only for Reference)

Kinase Assay: [1]

Assays for read-through of LUC premature termination codons Stock solutions of PTC124 (6 mM) are prepared in 100% DMSO HEK293 cells grown in a medium containing fetal bovine serum (FBS) and are stably transfected with LUC genes containing premature terminators at codon 190 (and 11 contextual variants thereof), treated with increasing concentrations of PTC124 for 16 hours, and assayed for luciferase activity. Luminescence of each culture relative to the control is quantified by standard procedures using a Viewlux CCD imager. Luminescence data are normalized to that produced with DMSO, and the fold suppression over background is calculated as (PTC124light units/DMSOlight units).

Animal Study: [2]

Animal Models Cftr-/- hCFTR-G542X transgenic mice
Formulation Dissolved in DMSO, and diluted in saline
Dosages ~60 mg/kg/day
Administration Subcutaneous injection or oral administration

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Welch EM, et al. Nature, 2007, 447(7140), 87-91.

[2] Du M, et al. Proc Natl Acad Sci U S A, 2008, 105(6), 2064-2069.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-18)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02758626 Not yet recruiting Epilepsy New York University School of Medicine|PTC Therapeutics April 2016 Phase 2
NCT02647359 Recruiting Aniridia PTC Therapeutics January 2016 Phase 2
NCT02456103 Enrolling by invitation Cystic Fibrosis PTC Therapeutics July 2015 Phase 3
NCT02409004 Not yet recruiting Healthy PTC Therapeutics March 2015 Phase 1
NCT02139306 Active, not recruiting Cystic Fibrosis PTC Therapeutics|Cystic Fibrosis Foundation Therapeutics|  ...more PTC Therapeutics|Cystic Fibrosis Foundation Therapeutics|European Cystic Fibrosis Society-Clinical Trial Network (ECFS-CTN) June 2014 Phase 3

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Chemical Information

Download Ataluren (PTC124) SDF
Molecular Weight (MW) 284.24
Formula

C15H9FN2O3

CAS No. 775304-57-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 57 mg/mL (200.53 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid

Customer Product Validation(6)


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Rating
Source J Clin Invest 2014 124(1), 111-6. Ataluren (PTC124) purchased from Selleck
Method Histology
Cell Lines Pax6<sup>Sey+/–</sup> mice
Concentrations 30 ug/g
Incubation Time P14
Results Daily subcutaneous injections of 30 ug/g ataluren or 6.25 ug/g gentamicin from P4 to P14 in Pax6Sey+/– mice. In mutant eyes, prior to treatment at P4, the cornea was thickened, there was a lenticular stalk in which the underdeveloped lens was attached to the cornea, and the retina was thickened and abnormally infolded at the ciliary margin.

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Rating
Source Hum Mol Genet 2014 23(8), 2005-22. Ataluren (PTC124) purchased from Selleck
Method Electron microscopy analysis
Cell Lines TPP1-FB1 cells
Concentrations 18 uM
Incubation Time 72 h
Results Moreover, commensurate with the increase in TPP1 activity achieved by PTC124 treatment, it also observed a significant impact on deceasing subunit c storage.

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Rating
Source Hum Mol Genet 2014 10.1093/hmg/ddu42. Ataluren (PTC124) purchased from Selleck
Method Immunocytochemistry
Cell Lines R120X RPE cells
Concentrations 10 ug/ml
Incubation Time 24 h
Results Plasma membrane localization of endogenous Gβ1 in R120X RPE cells was restored following treatment with G418 and PTC124, and co-localization with the plasma membrane marker wheat-germ agglutinin (WGA) was confirmed by both Pearson's and Mander's coefficients.

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Rating
Source Hum Mol Genet 2014 10.1093/hmg/ddu42. Ataluren (PTC124) purchased from Selleck
Method RT-qPCR, Western blot
Cell Lines R120X fibroblasts
Concentrations 10 ug/ml
Incubation Time 24 h
Results PTC124, could potentially restore some RP2 expression. Reverse transcriptase-quantitative PCR (RT-qPCR) showed that RP2 mRNA levels in R120X fibroblasts were ~80% lower than levels in male control cells, suggesting that the mutant RP2 R120X transcript is subjected to NMD. The most effective dose of PTC124 treatment (10 ug/ml) appeared to increase RP2 mRNA levels compared with untreated R120X cells. Treatment with G418 (750 uM dose) or PTC124 (10 ug/ml dose) led to an increase in RP2 protein to 20% and 13% of control cell levels, respectively.

Click to enlarge
Rating
Source Hum Mutat 2012 33, 973-80. Ataluren (PTC124) purchased from Selleck
Method qRT-PCR
Cell Lines fibroblasts
Concentrations 10/20 μM
Incubation Time
Results we measured mRNA levels in P1–P4 fibroblasts, and no significant differences were observed, except for sample P2 with G418 and PTC124.

Click to enlarge
Rating
Source Dr. Lu Tan of Children’s Hospital of Philadelphia. Ataluren (PTC124) purchased from Selleck
Method Quantitative RT-PCR analysis
Cell Lines fibroblasts
Concentrations 0-5 μM
Incubation Time 72 h
Results The real-time PCR results show that CPT1A mRNA expression remains minor fold change (less than 2 folds) in PTC124 treated cells compare to the untreated control cells after 72 hours of incubation.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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