Scientists use light to control cancer-fighting DNA molecules in living cells

<p>G-quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4-specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light-responsive G4-binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4-associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain,<strong> Q-Azo4F-C</strong>, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its <em>trans</em> and <em>cis</em> configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25-fold reversible cytotoxic activity. Immunostaining conducted with the structure-specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo-driven reversible regulation of G4 structures in lung cancer cells by <strong>Q-Azo4F-C</strong>. Our findings highlight the potential of light-responsive G4-binders in advancing precision cancer therapy through dynamic control of G4-mediated pathways.</p>