PTC124 | CAS:775304-57-9

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Name:PTC124; Ataluren
Cat. No. :CS-0503
CAS No. :775304-57-9
Formula:C15H9FN2O3
M. Wt. : 284.24
Solubility:DMSO: ≥ 52 mg/mL

PTC124 targets nonsense mutations, which insert a termination codon in the middle of the CFTR gene. IC50 & Target: CFTR[1]In Vitro: This premature “stop” signal (a class I mutation) prevents the cell from producing a full-length CFTR protein[1]. PTC124 (Ataluren)-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons[2]. In Vivo: PTC124 (Ataluren) activity, optimized using nonsense-containing reporters, promotes dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescues striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 is well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression[2]. To induce nonsense suppression and increase PPT1 enzyme activity, the read-through drug PTC124 (Ataluren) is given via intraperitoneal (i.p.) injection to male Cln1R151X mice at 2 months of age. These treatments are performed four times daily for 2 consecutive days in a proof-of-principle study. Used at 10 mg/kg, PTC124 increased PPT1 enzyme activity (P=0.0001 by unpaired t-test) and protein level (P=0.0014 by unpaired t-test) in the liver, but did not increase PPT1 enzyme activity or protein level in the cortex. This tissue-specific effect is likely due to the inability of PTC124 to breach the blood brain barrier (BBB), which decreased the bioavailability of PTC124 within the brain, and prevented PTC124 from reaching an efficacious concentration within the therapeutic window[3].

Miller JN, et al. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet. 2015 Jan 1;24(1):185-96. Welch EM, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007, 447(7140), 87-91. Pettit RS, et al. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11.