Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma.
Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma.
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DOI：
10.1021/acs.jmedchem.3c00094
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发表时间：
2023-03
影响因子：
7.3
通讯作者：
Xiu-Cai Chen;Gui-Xue Tang;Jing Dai;Le-Tian Dai;Tian-Ying Wu;Wen-Wei Li;Tian-Miao Ou;Zhishu Huang;Jia-Heng Tan;Shuo-Bin Chen
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作者：
Xiu-Cai Chen;Gui-Xue Tang;Jing Dai;Le-Tian Dai;Tian-Ying Wu;Wen-Wei Li;Tian-Miao Ou;Zhishu Huang;Jia-Heng Tan;Shuo-Bin Chen
NRAS突变促进肿瘤发生和耐药性。由于这种蛋白质通常被认为是一种不可治疗的靶标，因此迫切需要开发新的策略来抑制NRAS用于抗癌治疗。最近的报道表明，在NRAS mRNA的非翻译区形成的G-四链体（G4）结构可以下调NRAS翻译，这表明了一种潜在的NRAS抑制策略。在这里，我们开发了一种新的基于细胞的方法，使用G-四链体触发的荧光杂交探针大规模筛选NRAS G4配体，并成功地确定了临床上使用的药剂奥替尼啶作为一个有效的NRAS阻遏物。该化合物抑制NRAS翻译，阻断MAPK和PI 3 K-AKT信号传导，并引起伴随的细胞周期停滞、凋亡和自噬。它表现出比临床抗黑色素瘤药物更好的抗增殖作用，并能抑制异种移植小鼠模型中NRAS突变黑色素瘤的生长。我们的研究结果表明，奥替尼定可能是一种突出的抗NRAS突变型黑色素瘤药物，并代表了一种新的NRAS突变型黑色素瘤治疗选择。
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.