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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\u2032-UTR mRNA of the <jats:italic>KRAS<\/jats:italic> gene. Biophysical experiments showed that di-substituted IQc compounds are potent and selective <jats:italic>KRAS<\/jats:italic> G4 stabilizers. They preferentially inhibit the proliferation of <jats:italic>KRAS<\/jats:italic> mutant cancer cell lines (0.22 &lt; IC<jats:sub>50<\/jats:sub> &lt; 4.80 \u03bcM), down-regulate <jats:italic>KRAS<\/jats:italic> promoter activity in a luciferase reporter assay and reduce both KRAS mRNA and p21<jats:sup>KRAS<\/jats:sup> 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 <jats:italic>KRAS<\/jats:italic> expression. Overall, the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy.<\/jats:p>","DOI":"10.1038\/srep09696","type":"journal-article","created":{"date-parts":[[2015,4,8]],"date-time":"2015-04-08T16:22:16Z","timestamp":1428510136000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines"],"prefix":"10.1038","volume":"5","author":[{"given":"Jo\u00e3o","family":"Lavrado","sequence":"first","affiliation":[]},{"given":"Hugo","family":"Brito","sequence":"additional","affiliation":[]},{"given":"Pedro M.","family":"Borralho","sequence":"additional","affiliation":[]},{"given":"Stephan A.","family":"Ohnmacht","sequence":"additional","affiliation":[]},{"given":"Nam-Soon","family":"Kim","sequence":"additional","affiliation":[]},{"given":"Clara","family":"Leit\u00e3o","sequence":"additional","affiliation":[]},{"given":"S\u00edlvia","family":"Pisco","sequence":"additional","affiliation":[]},{"given":"Mekala","family":"Gunaratnam","sequence":"additional","affiliation":[]},{"given":"Cec\u00edlia M. 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