DNA G-quadruplexes and nonsense mutations as dual targets for small-molecule-based cancer therapy

DNA G-quadruplexes are non-canonical nucleic acid secondary structures enriched in promoter regions of several oncogenes, where they play a pivotal role in regulating gene transcription. Small molecules capable of selectively binding and stabilizing G4 structures have emerged as promising anticancer agents by repressing oncogene expression and inhibiting tumor cell proliferation. In parallel, nonsense mutations in tumor suppressor genes, such as TP53, generate premature termination codons (PTCs), resulting in truncated, nonfunctional proteins and promoting tumor progression by disrupting critical cellular processes. Translational readthrough-inducing drugs (TRIDs) represent an attractive strategy to restore full-length protein synthesis by promoting ribosomal readthrough of PTCs. Among them, the oxadiazole-based compounds NV848, NV914, and NV930 have demonstrated robust readthrough activity in several nonsense mutation related in vitro models. Here, we investigated the therapeutic potential of combining TRIDs with the DNA G-quadruplex stabilizer RB1 as a dual-targeted strategy simultaneously aimed at restoring p53 expression and suppressing oncogenic transcription.