KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines

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Title
KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines
Author(s)
J Lavrado; H Brito; P M Borralho; S A Ohnmacht; Nam-Soon Kim; C Leitao; S Pisco; M Gunaratnam; C M Rodrigues; R Moreira; S Neidle; A Paulo
Bibliographic Citation
Scientific Reports, vol. 5, pp. 9696-9696
Publication Year
2015
Abstract
KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable. To explore a new therapeutic strategy, a library of 5-methyl-indolo[3,2-c]quinoline derivatives (IQc) with a range of alkyldiamine side chains was designed to target DNA and RNA G-quadruplexes (G4) in the promoter and 5′-UTR mRNA of the KRAS gene. Biophysical experiments showed that di-substituted IQc compounds are potent and selective KRAS G4 stabilizers. They preferentially inhibit the proliferation of KRAS mutant cancer cell lines (0.22 < IC 50 < 4.80 μM), down-regulate KRAS promoter activity in a luciferase reporter assay, and reduce both KRAS mRNA and p21KRAS steady-state levels in mutant KRAS colon cancer cell lines. Additionally, IQcs induce cancer cell death by apoptosis, explained in part by their capacity to repress KRAS expression. Overall, the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy.
ISSN
2045-2322
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/srep09696
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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