Challenges in developing small-molecule quadruplex therapeutics

Abstract Quadruplex-binding small molecule compounds can produce a variety of cellular effects, including telomere dysregulation, inhibition of transcription and inhibition of translation. These last two depend on the location of the target quadruplex within an eukaryotic gene (promoter or untranslated region). It is apparent that of the likely 10,000 quadruplex targets in a human cancer cell, a large number are within cancer-relevant genes and thus are potential targets for therapeutic intervention. Numerous quadruplex-binding compounds have been shown to down-regulate expression of c-MYC and other cancer genes. It is unlikely though that these compounds directly bind to a single quadruplex and affect just a single gene. Whole-genome transcriptome profiling and genetic methods using hairpin RNA libraries have shown that the large number of genes typically down-regulated by quadruplex-binding compounds are enriched in putative quadruplex sequences, consistent with a model of multiple quadruplex targeting. Features of quadruplex-binding compounds required for eventual drug development are discussed. Case histories are presented for two quadruplex-binding compounds which affect telomere function in cancer cells and show in vivo activity against experimental cancer models. Neither have advanced beyond pre-clinical assessment due to off-target toxicity and narrow therapeutic windows. Case histories of two compounds with sensitivity for BRCA1/2 deficient cells that are currently in clinical trial are also presented, indicating the importance of patient profiling rather than target choice, for clinical success.