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

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 < IC50 < 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.

Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions

“…A small molecule capable of arresting the G-quadruplex structure that is located in the promoter region of an oncogene, brings in transcriptional repression of the gene610. This is a highly suggested therapeutic approach for treatment of different carcinomas in which these oncogenes are overexpressed10.…”

“…This is a highly suggested therapeutic approach for treatment of different carcinomas in which these oncogenes are overexpressed10. Among many oncogenes, VEGFA, BCL2 and KRAS are overexpressed in many types of cancer cells.…”

“…These are known as six hallmarks of cancer7. These important events are linked with G-quadruplex forming gene promoters including c-MYC8, c-KIT9 and KRAS10 (self-sufficiency), RB1 (insensitivity), BCL211 (evasion of apoptosis), VEGFA (angiogenesis)12 hTERT (limitless replication)13 and PDGFA (metastasis). G-quadruplex structures in oncogenic promoters are indicators of the six hallmarks of cancer.…”

Nucleic acid clamp-mediated recognition and stabilization of the physiologically relevant MYC promoter G-quadruplex

“…Luciferase experiments were replicated three times with internal duplicates measured within each experiment. Fold-changes induced by the clamps in the Del4 plasmid were normalized to any effects noted in the EV plasmid, as in (49). One-way ANOVA with post-hoc Tukey's test was employed to determine the statistical significance.…”

Naphthalene diimide‐derivatives G‐quadruplex ligands induce cell proliferation inhibition, mild telomeric dysfunction and cell cycle perturbation in U251MG glioma cells

“…In particular, G4 motifs are often located in oncogene promoters, thus suggesting a function responsible for such conservation during the genome evolution [3]. For instance, stabilized G4 in telomeric region hamper telomerase binding to telomeres and induce replication-mediated DNA damage at telomeres, hence determining telomere dysfunction [11], whereas stabilized G4 in gene promoters or in mRNA may modulate target gene expression [12][13][14][15]. Indeed, G4s can take numerous conformations and different strategies may be adopted to develop compounds with high structural selectivity for a particular G4, making them attractive druggable sites [1,4,5,[7][8][9].…”