CNRS, Institute of Chemistry of Nice (ICN), Université Côte d'Azur, 28 avenue Valrose, 06100 Nice, France.
Institut de Recherche Servier, 125 chemin de Ronde, 78290 Croissy-sur-Seine, France.
J Med Chem. 2023 Aug 10;66(15):10639-10657. doi: 10.1021/acs.jmedchem.3c00797. Epub 2023 Jul 14.
Noncoding RNAs (ncRNAs) play pivotal roles in the regulation of gene expression and represent a promising target for the development of new therapeutic approaches. Among these ncRNAs, microRNAs (miRNAs or miRs) are involved in the regulation of gene expression, and their dysregulation has been linked to several diseases such as cancers. Indeed, oncogenic miRNAs are overexpressed in cancer cells, thus promoting tumorigenesis and maintenance of cancer stem cells that are resistant to chemotherapy and often responsible for therapeutic failure. Here, we describe the design and synthesis of new small-molecule RNA binders able to inhibit the biogenesis of oncogenic miRNAs and target efficiently cancer stem cells. Through the biochemical study of their interaction with the target and thanks to intracellular assays, we describe the structure-activity relationships for this new series of RNA ligands, and we identify compounds bearing a very promising antiproliferative activity against cancer stem cells.
非编码 RNA（ncRNAs）在基因表达调控中发挥着关键作用，是开发新治疗方法的有前途的靶点。在这些 ncRNAs 中，microRNAs（miRNAs 或 miR）参与基因表达的调控，其失调与多种疾病（如癌症）有关。事实上，致癌 miRNA 在癌细胞中过度表达，从而促进肿瘤发生和维持对化疗有抗性的癌症干细胞，而这些癌症干细胞通常是导致治疗失败的原因。在这里，我们描述了新的小分子 RNA 结合物的设计和合成，这些小分子 RNA 结合物能够抑制致癌 miRNA 的生物发生，并有效地靶向癌症干细胞。通过对其与靶标的相互作用的生化研究，并借助细胞内测定，我们描述了这个新系列 RNA 配体的结构-活性关系，并确定了具有非常有前途的抗增殖活性的化合物，可针对癌症干细胞。
