Quadruplex nucleic acids as targets for anticancer therapeutics

Quadruplex nucleic acids — helical four-stranded structures known to form from guanine-rich nucleic acid sequences through Hoogsteen-type hydrogen bonding — were once just laboratory curiosities. However, they are now emerging from this rather obscure status to become important targets for small-molecule drugs, which can stabilize the quadruplex structures and thereby promote selective downregulation of gene expression and telomerase inhibition, and also activate DNA damage responses. Most of these quadruplex-binding small molecules can stabilize a range of cellular quadruplexes, as well as clusters of quadruplexes within a single gene or telomere, which could be an advantage. This widespread stabilization can generate a polygene response, and thus is able to simultaneously affect several key driver genes in human cancers, with potential therapeutic benefit. Quadruplex DNA structures were first observed more than 50 years ago, but have only relatively recently attracted interest for their role in the development of cancer. This Perspective considers attempts to selectively bind and stabilize these structures using small molecules, with the aim of developing anticancer therapeutics.