Potential translational readthough inducin drugs: an optimized design and synthesis of new chemical scaffolds

Genetic diseases can be caused by mutations, that lead to a change in the DNA sequence which can affect one gene or more, or alteration in the chromosome structure. Among different mutation types, a nonsense mutation results in the conversion of an amino-acid coding triplet into a premature stop codon (PTC) in the mRNA, leading to an impairment of the genetic product synthesis.[1] These mutations account for 11% of all genetic disease and affect 12% of tumor suppressor gene, underscoring the crucial importance of developing a treatment.[2] A novel treatment strategy for nonsense mutation is based on a pharmacological approach via molecules capable to induce the readthrough mechanism , known as TRIDs. Among different TRIDs structures, Ataluren, a small molecule with a 1,2,4-oxadiazole heterocyclic core [3], emerged as the only drug approved by EMA; notwithstanding its activity, many issues have been raised and the renewal for the authorization is in doubt. For this reasons the aim of this work is the identification of new chemical scaffolds and the evaluation of their capacity to induce translational readthrough. In order to find new chemical scaffolds to be employed as TRIDs here we apply a pharmacophore approach on active compounds that showed readthrough activity comparable or better than that of Ataluren. The validated pharmacophore model, produced through a structure-based approach, was used to screen public and “in-house” libraries and allowed to identify new hit compounds with various chemical scaffolds. These compounds have been synthesized and tested using the Luciferase assay to evaluate their capability of inducing translational readthrough.