NEW TRANSLATIONAL READTHROUGH INDUCING DRUGS RESCUING NONSENSE MUTATED TP53: STRATEGIES AGAINST CANCER

Nonsense mutations are point mutations that 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 mutations account for 11% of genetic diseases and affect 12% of tumor suppressor genes, among which TP53, one of the most frequently mutated tumor suppressor genes in human tumors [1]. TP53 gene encodes 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 [2]. The main consequence of its mutation in cancer is the loss of tumor suppressor function. More than half of cases of all human cancers are characterized by mutations in TP53 about, 10% of these mutations are nonsense mutations, underscoring the crucial importance of developing new treatments [3]. Several promising approaches to p53-based therapy have emerged in recent years, giving hope that TP53 alteration will finally be considered treatable, including translational readthrough (RT)- based therapy[4]. RT-based therapy is a prominent non-gene-specific strategy in nonsense mutation treatment. It’s based on the pharmacological induction of translational readthrough, which leads to the suppression of a stop codon at a post-transcriptional level by exploiting molecules called translational readthrough-inducing drugs (TRIDs)[5]. The RT-based therapy could potentially result in the recovery of full-length p53 protein, potentially reactivating its tumor-suppressing functions. In this work, we identified new chemical scaffolds capable of restoring the expression of a complete p53 protein. We developed a novel pharmacophore model using a ligand-based approach to discover potential TRIDs. After synthesizing these new compounds, we tested their ability to induce translational readthrough using a Firefly luciferase (FLuc) assay in HeLa cells with nonsense mutation. The best-performing molecules, selected based on in-silico and in-vitro toxicity and in-silico ADME (absorption, distribution, metabolism, excretion) properties, were evaluated for their effectiveness in producing full-length p53 protein.