Rescuing TP53 from nonsense: novel triazoles for translational readthrough via optimized drug design.

Nonsense mutations introduce premature termination codons (PTCs), leading to mRNA degradation and the production of truncated, non-functional proteins. These mutations account for approximately 10% of TP53 alterations, a key driver in over 50% human cancers. Effective therapeutic strategies to restore full-length functional p53 remain limited. Here, using an optimized drug design workflow that integrates in silico approaches, we identified and characterized a novel class of 1,2,4-triazole-based translational readthrough-inducing drugs (TRIDs) capable of restoring full-length p53 protein in cells harboring the R213X nonsense mutation. We synthesized and screened four compounds (IP14, IP15, IP17, IP18) with favorable in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. All four compounds successfully rescued p53 expression in H1299 R213X cells, outperforming Ataluren and matching G418 at significantly lower concentrations. The restored p53 exhibited nuclear localization upon genotoxic stress and induced transcription of canonical targets. These findings highlight the therapeutic potential of these compounds for treating TP53 nonsense mutations in cancer and lay the groundwork for the development of targeted nonsense mutation-specific treatment for a wide range of pathologies, including new emergent p53 related diseases.