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Background  A guanine-rich strand within the promoter of the  KRAS  gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of  KRAS  transcription. We have previously identified indolo[3,2- b ]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the  KRAS  promoter and subsequent down-regulation of gene expression.    Methodology/Principal Findings  IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced  KRAS  promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC 50  < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A compounds significantly reduced  KRAS  mRNA and protein steady-state levels at IC 50  concentrations, and increased p53 protein steady-state levels and cell death by apoptosis in HCT116 cells (mut  KRAS , wt  p53 ). Furthermore, KRAS silencing in HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic cell lines induced a higher level of cell death, and a higher IQ3A-induced cell death in HCT116 p53(+/+) compared to HCT116 p53(-/-).    Conclusions  Herein we provide evidence that G4 ligands such as IQ3A compounds can target G4 motifs present in  KRAS  promoter, down-regulate the expression of the mutant  KRAS  gene through inhibition of transcription and translation, and induce cell death by apoptosis in colon cancer cell lines. Thus, targeting KRAS at the genomic level with G4 ligands may be a new anticancer therapy strategy for colon cancer.

Targeting KRAS Oncogene in Colon Cancer Cells with 7-Carboxylate Indolo[3,2-b]quinoline Tri-Alkylamine Derivatives