Sanchez-Martin, VictoriaSchneider, David A.Ortiz-Gonzalez, MatildeSoriano-Lerma, AnaLinde-Rodriguez, AngelPerez-Carrasco, VirginiaGutierrez-Fernandez, JoseCuadros, MartaGonzalez, CarlosSoriano, MiguelGarcia-Salcedo, Jose A.2025-01-072025-01-072021-11-182451-9448https://hdl.handle.net/10668/26375Guanine quadruplexes (G4s) are non-canonical nucleic acid structures commonly found in regulatory genomic regions. G4 targeting has emerged as a therapeutic approach in cancer. We have screened naphthalene-diimides (NDIs), a class of G4 ligands, in a cellular model of colorectal cancer (CRC). Here, we identify the leading compound T5 with a potent and selective inhibition of cell growth by high-affinity binding to G4s in ribosomal DNA, impairing RNA polymerase I (Pol I) elongation. Consequently, T5 induces a rapid inhibition of Pol I transcription, nucleolus disruption, proteasome-dependent Pol I catalytic subunit A degradation and autophagy. Moreover, we attribute the higher selectivity of carbohydrate-conjugated T5 for tumoral cells to its preferential uptake through the overexpressed glucose transporter 1. Finally, we succinctly demonstrate that T5 could be explored as a therapeutic agent in a patient cohort with CRC. Therefore, we report a mode of action for these NDIs involving ribosomal G4 targeting.enTranscriptionBindingVisualizationTransportersVitroresearch article34166611open access10.1016/j.chembiol.2021.05.021http://www.cell.com/article/S245194562100266X/pdf722642500006