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Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma
Xiu-Cai Chen1, Gui-Xue Tang1, Jing Dai1
1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.
Insights
Octenidine, a novel NRAS G4 ligand, effectively suppresses NRAS translation and inhibits NRAS-mutant melanoma growth. This discovery offers a promising new therapeutic option for melanoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- NRAS mutations drive cancer and drug resistance, posing a significant therapeutic challenge.
- The NRAS protein is considered an undruggable target, necessitating innovative suppression strategies.
- A G-quadruplex (G4) structure in NRAS mRNA offers a potential target for NRAS suppression.
Purpose of the Study:
- To develop a method for screening NRAS G4 ligands.
- To identify novel NRAS repressors for anticancer therapy.
- To evaluate the therapeutic potential of identified compounds against NRAS-mutant melanoma.
Main Methods:
- Developed a cell-based screening assay using a G-quadruplex-triggered fluorogenic hybridization probe.
- Screened for NRAS G4 ligands to identify NRAS repressors.
- Investigated the effects of Octenidine on NRAS translation, signaling pathways, and melanoma cell behavior in vitro and in vivo.
Main Results:
- Identified Octenidine, a clinical agent, as a potent NRAS repressor.
- Octenidine suppressed NRAS translation, inhibited MAPK and PI3K-AKT signaling, and induced cell cycle arrest, apoptosis, and autophagy.
- Octenidine demonstrated superior antiproliferation effects compared to existing melanoma agents and inhibited tumor growth in a xenograft model.
Conclusions:
- Octenidine is a potent suppressor of NRAS translation and signaling.
- Octenidine exhibits significant anti-melanoma activity against NRAS-mutant tumors.
- Octenidine represents a promising therapeutic candidate for NRAS-mutant melanoma.
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