Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5'-UTR RNA G-Quadruplexes.
Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5'-UTR RNA G-Quadruplexes.
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DOI：
10.1021/acs.jmedchem.3c01773
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发表时间：
2024-01
影响因子：
7.3
通讯作者：
Mao-Lin Li;Le-Tian Dai;Zhuo-Yu Gao;Jia-Tong Yan;Shu-Min Xu;Jia-Heng Tan;Zhishu Huang;Shuo-Bin Chen;Xiu-Cai Chen
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文献类型：
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作者：
Mao-Lin Li;Le-Tian Dai;Zhuo-Yu Gao;Jia-Tong Yan;Shu-Min Xu;Jia-Heng Tan;Zhishu Huang;Shuo-Bin Chen;Xiu-Cai Chen
过度活化的KRAS突变促进肿瘤发生，并代表了癌症治疗的有吸引力的靶点。虽然共价抑制剂已显示出对KRASG 12 C突变体的临床益处，但非G12 C突变体的进展仍然有限，这突出了对泛KRAS抑制剂的迫切需求。KRAS mRNA的5 '非翻译区中的RNA G-四链体（rG 4）可以调节KRAS翻译，使其成为泛KRAS抑制剂开发的有希望的靶标。在此，我们设计并合成了50种新型香豆素-喹啉衍生物，利用我们以前开发的rG 4特异性配体，QUMA-1。值得注意的是，几种化合物作为泛KRAS翻译抑制剂对癌细胞表现出有效的抗增殖活性。其中，15 a在稳定KRAS rG 4、抑制KRAS翻译并因此调节MAPK和PI 3 K-AKT通路方面显示出优异的能力。15 a诱导细胞周期停滞，促使KRAS驱动的癌细胞凋亡，并有效抑制KRAS突变异种移植模型中的肿瘤生长。这些发现强调了15 a作为泛KRAS翻译抑制剂的潜力，为靶向各种KRAS驱动的癌症提供了一种新的有希望的方法。
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.