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

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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∗EGFPNYPVNYtZTnWwY4Tpc44hSXO|YYm=M33qNFIxyqEQvF2=NYC1NGsxPzMEoHlCpC=>NXjqe485TE2VTx?=MUjy[ZN2dHS|IHnuJIEhe2mpbnnmbYNidnRiaX7jdoVie2ViaX6gcYVlcWGwIIDlZYsh\my3b4Lld4NmdmOnMmW4NlMxPDFzOEm=
Mut−/−MUTStop+/−MYHGeY5kfGmxbjDBd5NigQ>?M4DYNVIxyqEQvF2=NWPhcnhRPzMEoHlCpC=>NGKxcnFFVVORMUnpcoNz\WG|ZYOgeIhmKGGvb4XueEBw\sLiTWXUxsBuWk6DM124WVI{ODRzMUi5
HEK293TMkHqSpVv[3Srb36gRZN{[Xl?NH74NY8yOCEEtXevcYw>NFTtfWZFVVORMmPDdoV{fG:{ZYOg[pVtdC2uZX7neIghcGG{bX;ubY4h[TFiKPMIwFgxKGuGYTmgbY4heC6UM{HYMZRz[W6|ZnXjeIVlKGOnbHzzNYPrU4F2OjNyMke2OFA>
ML1MVLGeY5kfGmxbjDBd5NigQ>?MWSzMlMwOTEEoN88US=>MUW0PEBpMmXESG1UVw>?NXvIboo6cW6lcnXhd4V{KEGUU1KgZYN1cX[rdIm=NUPQcGFZOjJ7N{G5OVk>
ML2M3z0PWZ2dmO2aX;uJGF{e2G7M1voWlMvOy9zMNMg{txOM{fHNFQ5KGh?NUj3WHNITE2VTx?=MkfYbY5kemWjc3XzJGFTW0JiYXP0bZZqfHl?MmDXNlI6PzF7NUm=

... 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 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02819557 Recruiting Duchenne Muscular Dystrophy PTC Therapeutics June 2016 Phase 2
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

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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

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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