Translational readthrough approach to fight nonsense in cancer: design and synthesis of new trids rescuing P53

Genetic disorders are caused by mutations that can lead to a nucleotidic modification in DNA sequences, which can involve one or more gene, or abnormalities in chromosome structure. Among different type of mutations, nonsense mutations cause the conversion of an amino-acid coding triplet in a Premature Termination codon (PTC) leading to a decrease in cytosolic mRNA level and a premature termination of the translation with production of truncated and non- functional protein. Nonsense mutation account for the 11% of genetic disease and affect 12% of tumor suppressor genes, among which TP53, one of the most frequently mutated tumor suppressor gene in human tumors. TP53 encode for p53, a transcription factor, known as «the guardian of the genome», that plays different roles in the cell including: antiproliferative activities, DNA repair, apoptosis induction and senescence induction. More than half of cases of all human cancers are characterized by mutations in TP53, in this respect, 10% are nonsense mutations, underscoring the crucial importance of developing new treatment. A prominent strategy in nonsense mutation treatment is based on the pharmacological inducing of translational readthrough (RT) , that leads to the suppression of a stop codon at a post-transcriptional level exploiting molecules called translational readthrough inducing drugs (TRIDs). In this work we identified new chemical scaffolds containing an 1,2,4-triazolic heterocylic core through the development of a new pharmacophore model. After the synthesis of the new compounds we assessed their ability to induce translational readthrough with a preliminary biological screening using the Firefly luciferase assay (FLuc). The best performing molecules were chosen to determine the efficacy in promoting the production of a complete length p53 protein.