The overwhelming majority of DNA in the human genome is double-stranded. However, regions comprising several short guanine-tracts are capable of forming higher-order structures, termed quadruplexes. These are not distributed uniformly throughout the genome but are overrepresented in regulatory regions of proliferative genes, in particular those involved in human cancers. Quadruplexes are normally transient and can be read through by polymerases or unwound by helicases. However, they can be stabilized by appropriate quadruplex-selective small molecules and then become effective impediments to transcription, replication or translation.
Crystal-structure analysis has enabled the features of several quadruplex-small molecule complexes to be defined and subsequently used for structure-based optimization of quadruplex affinity. A small-molecule compound derived in this way will be described, and its pathway to pre-clinical evaluation will be described. it is not specific for a single quadruplex in the genome, but down-regulates a number of key-quadruplex-related genes. This multi-targeting enables the compound to show potent anti-cancer activity in in vivo models for genetically complex cancers such as pancreatic ductal adenocarcinoma, which to date has been one of the most intractable of all cancers to treat.
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