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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 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.

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