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

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 th...

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Published in:Scientific reports 2015-04, Vol.5 (1), p.9696-9696, Article 9696
Main Authors: Lavrado, João, Brito, Hugo, Borralho, Pedro M, Ohnmacht, Stephan A, Kim, Nam-Soon, Leitão, Clara, Pisco, Sílvia, Gunaratnam, Mekala, Rodrigues, Cecília M P, Moreira, Rui, Neidle, Stephen, Paulo, Alexandra
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Cell death
Cell Line, Tumor
Cell Proliferation - drug effects
Colon cancer
Colorectal cancer
Deoxyribonucleic acid
DNA
Dose-Response Relationship, Drug
Down-Regulation
Drug Stability
G-Quadruplexes
Gene Expression Regulation, Neoplastic - drug effects
Genes, ras
GTP-binding protein
Humans
Indoles - chemistry
K-Ras protein
Molecular Structure
mRNA
Oncogenes
Promoter Regions, Genetic
Quinolines
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Tumor cell lines
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Summary: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 < IC50 < 4.80 μM), down-regulate KRAS promoter activity in a luciferase reporter assay, and reduce both KRAS mRNA and p21(KRAS) 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
2045-2322
DOI:10.1038/srep09696