G-Quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells

McLuckie, Keith I. E., Waller, Z.A.E., Sanders, Deborah A., Alves, David, Rodriguez, Raphaël, Dash, Jyotirmayee, McKenzie, Grahame J., Venkitaraman, Ashok R. and Balasubramanian, Shankar (2011) G-Quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells. Journal of the American Chemical Society, 133 (8). pp. 2658-2663.

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There is considerable interest in the structure and function of G-quadruplex nucleic acid secondary structures, their cellular functions, and their potential as therapeutic targets. G-Quadruplex sequence motifs are prevalent in gene promoter regions and it has been hypothesized that G-quadruplex structure formation is associated with the transcriptional status of the downstream gene. Using a functional cell-based assay, we have identified two novel G-quadruplex ligands that reduce the transcription of a luciferase reporter driven from the G-quadruplex-containing c-KIT promoter. We have further shown that endogenous c-KIT expression in a human gastric carcinoma cell line is also reduced on treatment with these molecules. Biophysical analysis using surface plasmon resonance has shown that these molecules preferentially bind with high affinity to one of the two G-quadruplex sequences in the c-KIT promoter over double-stranded DNA. This work highlights the utility of cell-based reporter assays to identify new G-quadruplex binding molecules that modulate transcription and identifies benzo[a]phenoxazine derivatives as potential antitumor agents.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User: Rachel Smith
Date Deposited: 17 Mar 2011 14:38
Last Modified: 26 Jul 2023 05:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/26564
DOI: 10.1021/ja109474c

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