2,6 -二取代吲哚衍生物作为METTL3抑制剂的设计、合成和生物学评价

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-06 DOI:10.1016/j.ejmech.2025.118134

Ruoyang Miao , Chunxia Liu , Xianbin Li , Ning Wang , Linnan Zhao , Guanghe Zhu , Ruiying Zhu , Han Wei , Weiyan Cheng , Xin Tian

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引用次数: 0

摘要

METTL3 （Methyltransferase Like 3）由于其在RNA甲基化修饰中的关键作用，近年来引起了人们的广泛关注，成为治疗癌症的一种新的、极具前景的治疗靶点。在这里，我们报道了2,6 -二取代吲哚衍生物作为METTL3抑制剂的优化和评价。代表性化合物16e对METTL3的IC50值为0.49±0.30 nM。分子动力学模拟证实了16e与METTL3的结合。在体外实验中，16e显著降低急性髓性白血病MOLM-13细胞和卵巢癌SKOV3细胞中的m6A水平，显著抑制细胞增殖，诱导细胞凋亡，抑制细胞迁移，下调m6A下游靶基因c-MYC和BCL2的表达。此外，化合物16e在SKOV3异种移植瘤模型中表现出良好的药动学特征和抗肿瘤效果。总的来说，这项研究为开发新的癌症治疗方法提供了一个有希望的候选化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design, synthesis, and biological evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors

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Design, synthesis, and biological evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors

METTL3 (Methyltransferase Like 3) has garnered significant attention in recent years due to its pivotal role in RNA methylation modification, emerging as a novel and highly promising therapeutic target for the treatment of cancer. Here, we report the optimization and evaluation of 2, 6-di-substituted indole derivatives as METTL3 inhibitors. The representative compound 16e showed an IC₅₀ value of 0.49 ± 0.30 nM against METTL3. Molecular dynamics simulation confirmed that the binding of 16e to METTL3. In vitro assays, 16e significantly reduced m⁶A levels in acute myeloid leukemia MOLM-13 cells and ovarian cancer SKOV3 cells, markedly inhibited cell proliferation, induced cells apoptosis, suppressed cells migration, and downregulated the expression of m⁶A downstream target genes c-MYC and BCL2. Additionally, compound 16e showed favorable pharmacokinetic characteristics and good antitumor efficacy in a SKOV3 xenograft model. Collectively, this study provides a promising candidate compound for the development of new therapeutics for cancer treatment.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.