The concept of G-quadruplex ligands as novel gene regulators and potential anticancer drugs

Time: To be announced
To be announced
 Stephen Neidle


The human genome is not entirely duplex DNA. Instead, there exists numerous islands of G-rich sequence that are capable of folding into higher-order four-stranded structures, termed quadruplexes. These are not uniformly distributed throughout the genome but are notably overrepresented in oncogene promoter sequences. When stabilised, these quadruplexes can be impediments to transcription and thus represent a novel class of gene-targeted anticancer agents. It is now 24 years since the first report of a small-molecule compound stabilising quadruplex DNA and having a potentially therapeutic effect on an anti-cancer target. Many such agents have been subsequently devised, with some demonstrating anti-tumour activity in animal models. A few are now progressing beyond this stage into clinical evaluation in humans.

Our own efforts, as a multidisciplinary academic group, have focused on compounds based on a naphthalenediimide core, with three or four substituents, and an emphasis on pancreatic cancer (PDAC). Current lead compounds show high potency against a range of PDAC cell lines, including chemo-resistant ones. Transcriptome RNA-seq technology has been used to elucidate the quadruplex targets of these compounds in the human genome, and to rationalise activity in chemo-resistant cells. The pathway to these compounds has involved an integrated chemistry and pharmacology approach, to also optimise drug-like features. These lead compounds, at least at first glance, appear to be very non-drug-like: their biology has shown that first appearances can be deceptive and that they are effective against several in vivo PDAC models.
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