product name Ataluren (PTC124)
Description: Ataluren (also known as 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). Ataluren is currently being investigated for use in patients with nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD) and cystic fibrosis (nmCF).
References: Nature. 2007 May 3;447(7140):87-91; Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2064-9.
284.24
Formula
C15H9FN2O3
CAS No.
775304-57-9
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 57 mg/mL (200.5 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
1% DMSO+30% polyethylene glycol+1% Tween 80: 30mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19406506
| In Vitro |
In vitro activity: 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. Kinase Assay: Cell Assay: Cultured HEK293 cells harbouring UAA, UAG or UGA LUC-190 nonsense alleles were treated with increasing concentrations of PTC124 for 16 h, and assayed for luciferase activity. PTC124 promoted dose-dependent readthrough of all three nonsense codons. Levels of suppression correlated inversely with established termination efficiencies, with the highest readthrough at UGA, followed by UAG and then UAA. The minimal concentration of PTC124 showing discernable readthrough was 0.01–0.1 μM, whereas the concentration promoting maximal activity was approximately 3 μM. |
|---|---|
| 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. 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. |
| Animal model | Cftr-/- hCFTR-G542X transgenic mice |
| Formulation & Dosage | Dissolved in DMSO, and diluted in saline; 60 mg/kg/day; s.c. injection or oral administration |
| References | Nature. 2007 May 3;447(7140):87-91; Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2064-9. |
