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Title 

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

Authors 

J LavradoH BritoP M BorralhoS A OhnmachtNam-Soon KimC LeitaoS PiscoM GunaratnamC M RodriguesR MoreiraS NeidleA Paulo

Publisher 

Nature Publishing Group

Issue Date 

2015

Citation 

Scientific Reports, vol. 5, no. 0, pp. 9696-9696

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

Link 

http://dx.doi.org/10.1038/srep09696

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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