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Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment

2021; Elsevier BV; Volume: 28; Issue: 11 Linguagem: Inglês

10.1016/j.chembiol.2021.05.021

2451-9456

Victoria Sánchez-Martín, David A. Schneider, Matilde Ortiz-González, Ana Soriano‐Lerma, Ángel Linde-Rodríguez, Virginia Pérez‐Carrasco, José Gutiérrez Fernández, Marta Cuadros, Juan Carlos Morales, Carlos González, Miguel Soriano, José A. García‐Salcedo,

RNA and protein synthesis mechanisms

Guanine 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.