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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.
Highlights
KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable
Structure-activity relationships established on the basis of increased Tm determined by Fluorescence resonance energy transfer (FRET) were in agreement with those previously reported for IQb series of compounds[22]
The FRET competition experiments showed that 3e binds preferentially to KRAS21R compared to the human telomeric 21-mer G4 sequence (Figure 3)
Summary
KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable. Several approaches to pharmacological inhibition of RAS family oncoproteins, of KRAS, have been reported over the past three decades These included development of direct inhibitors of KRAS mutated proteins, blocking KRAS membrane association and targeting KRAS downstream effectors or upstream activator EGFR2. We have previously demonstrated that miR143 reduces KRAS expression, chemo-sensitizes colon cancer cells to 5-fluorouracil[8] and reduces tumour growth in vivo with increased apoptosis and reduced proliferation[9]. Such approaches have in particular delivery problems as well as potential off-target effects. G4 forming motifs have been located in the 59 untranslated region (UTR) of KRAS and NRAS mRNA and shown to be involved in translation inhibition[14,15]
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