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Updated: Dec 23, 2025
Single-molecule Manipulation of G-quadruplexes by Magnetic Tweezers
Published on: September 19, 2017
Targeting the KRAS oncogene: Synthesis, physicochemical and biological evaluation of novel G-Quadruplex DNA binders
Federica D'Aria1, Vincenzo Maria D'Amore1, Francesco Saverio Di Leva1
1Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, Italy.
Abstract:
The oncogene KRAS is involved in the pathogenesis of many tumors such as pancreatic, lung and colorectal cancers, thereby representing a relevant target for the treatment of these diseases. The KRAS P1 promoter contains a nuclease hypersensitive, guanine-rich sequence able to fold into a G-quadruplex motif (G4). The stabilization of this G4 structure by small molecules is emerging as a feasible approach to downregulate KRAS expression. Here, a set of novel stabilizing molecules was identified through a virtual screening campaign on the NMR structure of the 22-mer KRAS G4. The most promising hits were then submitted to structure-activity relationships studies which allowed improving their binding affinity and selectivity over double helix DNA and different G4 topologies. The best derivative (19) underwent fluorescence titration experiments and further computational studies to disclose its binding mechanism to KRAS G4. Finally, biological assays showed that this compound is capable to reduce the viability of colorectal cancer cells in which mutated KRAS acts as a driver oncogene. Thus, 19 might represent the prototype of a new class of drugs for the treatment of tumors that, expressing mutated forms of KRAS, are refractory to current therapeutic regimens.
Insights
Researchers identified a novel molecule that stabilizes a G-quadruplex (G4) structure in the KRAS oncogene promoter. This stabilization effectively reduces cancer cell viability, offering a potential new therapeutic strategy for KRAS-driven cancers.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- The KRAS oncogene is implicated in the development of various cancers, including pancreatic, lung, and colorectal cancers.
- The KRAS P1 promoter harbors a guanine-rich sequence that can form a G-quadruplex (G4) structure.
- Stabilizing the KRAS G4 motif with small molecules is a promising strategy to inhibit KRAS expression.
Purpose of the Study:
- To identify novel small molecules that stabilize the KRAS G4 structure.
- To optimize these molecules for improved binding affinity and selectivity.
- To evaluate the therapeutic potential of the lead compound in KRAS-driven cancer models.
Main Methods:
- Virtual screening of a compound library against the KRAS G4 NMR structure.
- Structure-activity relationship studies to refine lead compounds.
- Fluorescence titration and computational studies to elucidate binding mechanisms.
- In vitro biological assays to assess effects on cancer cell viability.
Main Results:
- Identification of a novel series of KRAS G4 stabilizing molecules.
- Optimization led to derivative 19 with enhanced binding affinity and selectivity.
- Compound 19 demonstrated a mechanism of binding to the KRAS G4.
- Biological assays confirmed that compound 19 reduces the viability of colorectal cancer cells driven by mutated KRAS.
Conclusions:
- Compound 19 is a potent KRAS G4 stabilizer with anti-cancer activity.
- This molecule may serve as a prototype for a new class of drugs targeting KRAS-mutated cancers.
- This approach offers a potential treatment for cancers refractory to current therapies.
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