化学
香豆素
翻译(生物学)
核糖核酸
克拉斯
非翻译区
组合化学
计算生物学
立体化学
生物化学
信使核糖核酸
有机化学
突变
基因
生物
作者
Maolin Li,Le-Tian Dai,Zhiliang Gao,Jia-Tong Yan,Shumin Xu,Jia‐Heng Tan,Shuo-Bin Chen,Shuo-Bin Chen,Xiu‐Cai Chen
标识
DOI:10.1021/acs.jmedchem.3c01773
摘要
Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRASG12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1. Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.
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