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.

鸟嘌呤四链体 (G4) 是在调控基因组区域中常见的非规范核酸结构。 G4 靶向已成为癌症的一种治疗方法。我们在结直肠癌 (CRC) 细胞模型中筛选了萘二酰亚胺 (NDI)，一类 G4 配体。在此，我们鉴定出主要化合物 T5，它通过与核糖体 DNA 中的 G4 高亲和力结合，削弱 RNA 聚合酶 I (Pol I) 的延伸，从而有效、选择性地抑制细胞生长。因此，T5 诱导快速抑制 Pol I 转录、核仁破坏、蛋白酶体依赖性 Pol I 催化亚基 A 降解和自噬。此外，我们将碳水化合物缀合的 T5 对肿瘤细胞的更高选择性归因于其通过过度表达的葡萄糖转运蛋白 1 的优先摄取。最后，我们简洁地证明 T5 可以作为 CRC 患者队列的治疗剂进行探索。因此，我们报告了这些涉及核糖体 G4 靶向的 NDI 的作用模式。