KRAS is a well-validated drug target for anti-cancer therapy, yet no clinically useful drugs that directly inhibit its function currently exist. We aim to target KRAS at the transcriptional level, through DNA secondary structures. The proximal promoter of the KRAS gene contains a GC-rich nuclease hypersensitivity site with three potential DNA secondary structure-forming sequences: the Far-, Mid-, and Near-regions. As a result of transcription-induced negative superhelicity, these regions can open up to form unique secondary structures: G-quadruplexes on the G-rich strand and i-Motifs on the C-rich strand. While G-quadruplexes in the promoter region of proto-oncogenes have the potential to silence transcription, i-Motifs have the potential to act as transcriptional activators. Thus, compounds capable of binding to and stabilizing G-quadruplexes or destabilizing i-Motifs could decrease gene expression. To date, we have developed a series of quindoline compounds that can either stabilize or destabilize the various G-quadruplexes forming in the KRAS promoter. Our results show that only those compounds that stabilize the Far-region G-quadruplex are capable of modulating KRAS gene transcription. We have also identified compounds capable of destabilizing the Mid-region i-Motif in favor of a hairpin species. These results will be discussed in terms of a strategy to silence KRAS gene expression by targeting either the G-quadruplex or the i-Motif structures.

Controlling KRAS gene expression through drug targeting of DNA secondary structures

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.