ataluren   Click here for help

GtoPdb Ligand ID: 7341

Synonyms: PTC124
Approved drug PDB Ligand
ataluren is an approved drug (EMA (2014))
Compound class: Synthetic organic
Comment: Ataluren is a compound in an emerging class of chemicals which induce ribosomal readthrough. This developing pharmaceutical intervention has been termed 'readthrough strategy'. Clinically, this type of compound has potential benefit in the treatment of genetic disorders associated with loss of functional protein due to nonsense or PTC mutations, such as certain types of muscular dystrophy, cystic fibrosis and many cancers [1,4].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 3
Topological polar surface area 76.22
Molecular weight 284.06
XLogP 3.88
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES Fc1ccccc1c1onc(n1)c1cccc(c1)C(=O)O
Isomeric SMILES Fc1ccccc1c1onc(n1)c1cccc(c1)C(=O)O
InChI InChI=1S/C15H9FN2O3/c16-12-7-2-1-6-11(12)14-17-13(18-21-14)9-4-3-5-10(8-9)15(19)20/h1-8H,(H,19,20)
InChI Key OOUGLTULBSNHNF-UHFFFAOYSA-N
No information available.
Summary of Clinical Use Click here for help
This drug was granted orphan designation by the European Medicines Agency (EMA) in 2005, and full apporval in 2014 for the treatment of Duchenne muscular dystrophy (DMD). Many clinical trials have been further assessing the efficacy of this drug in patients with nonsense mutation dystrophinopathies. Results from clinical trials testing ataluren have been reported [2] and more trials are underway. Click here to view current clinical trials of ataluren/PTC124 registered at ClinicalTrials.gov. Trial NCT02090959 is a confirmatory Phase 3 extension study in 220 patients with nonsense mutation dystrophinopathy which is a 96 week trial due for completion in mid-June 2014.
Ataluren is also being investigated for use in patients with nonsense mutation cystic fibrosis in Phase 3 studies (NCT00803205 and NCT01140451). A Phase 2a study in patients with nonsense mutation hemophilia A and B (NCT00947193) has been suspended.

A note of caution: The US FDA has rejected applications for approval of ataluren as it has repeatedly failed to show statistically significant results, failing both a Phase 2b study for DMD as well as a Phase 3 study for cystic fibrosis. The number of failures in late stage trials suggests that the only conclusion to be made is that ataluren is not clinically effective, despite being based on a sound biological mechanism. Read the In The Pipeline blogpost 'Bad News-But Not the Unexpected Kind' for further comments and debate around ataluren's future.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Studies have shown that the mechanism of action involves suppression of ribosome-induced termination of protein translation at premature termination codons (PTCs) whilst still recognising genuine stop codons [4]. By increasing the ability of the ribosome to ignore PTCs, increased amounts of functional full-length proteins are produced. However, the validity of the claimed action of this chemical has been questioned [3].
In Duchenne muscular dystrophy (DMD) the dystrophin gene carries a PTC in around 10 to 15% of patients.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT00803205 Study of Ataluren (PTC124™) in Cystic Fibrosis Phase 3 Interventional PTC Therapeutics
NCT00947193 Study of Ataluren (PTC124®) in Hemophilia A and B Phase 2 Interventional PTC Therapeutics
NCT01140451 Extension Study of Ataluren (PTC124) in Cystic Fibrosis Phase 3 Interventional PTC Therapeutics
NCT02090959 An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy Phase 3 Interventional PTC Therapeutics