Quadruplex Ligands in Cancer Therapy

SIMPLE SUMMARY: Four-stranded nucleic acid secondary structures (quadruplexes) including DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs display key regulatory functions in the human genome. Quadruplexes play an important role in telomere lengthening and the expression control of several cancer-related genes. In this context, quadruplex ligands are considered as potential strategies for anticancer drug discovery. Previous reviews are mainly focused on ligands targeting DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs in a separate way, hindering a holistic study. The present review overcomes this limitation by providing a general overview of the recent research on ligands targeting the three different quadruplex structures in cancer. ABSTRACT: Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.