Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5′-UTR RNA G-Quadruplexes,Journal of Medicinal Chemistry

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Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5′-UTR RNA G-Quadruplexes
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-25 , DOI: 10.1021/acs.jmedchem.3c01773
Mao-Lin Li ₁ , Le-Tian Dai ₁ , Zhuo-Yu Gao ₁ , Jia-Tong Yan ₁ , Shu-Min Xu ₁ , Jia-Heng Tan ₁ , Zhi-Shu Huang ₁ , Shuo-Bin Chen ₁ , Xiu-Cai Chen _{1,

2}

Affiliation

Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRAS^G12C 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.

中文翻译：

通过靶向 5'-UTR RNA G-四链体发现新型香豆素-喹啉衍生物作为泛 KRAS 翻译抑制剂

过度激活的 KRAS 突变会促进肿瘤发生，是癌症治疗的有吸引力的靶点。虽然共价抑制剂已显示出针对 KRAS ^G12C突变体的临床益处，但非 G12C 突变体的进展仍然有限，凸显了对泛 KRAS 抑制剂的迫切需求。 KRAS mRNA 5′非翻译区的 RNA G 四链体 (rG4) 可以调节 KRAS 翻译，使其成为泛 KRAS 抑制剂开发的有希望的靶点。在此，我们利用我们之前开发的 rG4 特异性配体QUMA-1设计并合成了 50 种新型香豆素-喹啉鎓衍生物。值得注意的是，几种化合物作为泛 KRAS 翻译抑制剂表现出有效的抗癌细胞增殖活性。其中， 15a在稳定KRAS rG4、抑制 KRAS 翻译、从而调节 MAPK 和 PI3K-AKT 通路方面表现出卓越的能力。 15a诱导细胞周期停滞，促进 KRAS 驱动的癌细胞凋亡，并在 KRAS 突变异种移植模型中有效抑制肿瘤生长。这些发现强调了15a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颖且有前景的方法。

更新日期：2024-01-25

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