A Nucleoside Analogue Featuring a C3′-Stereogenic All-Carbon Quaternary Center as a Bioenergetic Disruptor of KRAS-Mutated Pancreatic Cancer Cells

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI:10.1021/acsmedchemlett.5c00378

Houda Tantawi, Philippe Mochirian, Mathieu Truong, Janie Beauregard, Laura Collins, Georges Kanaan, Hiba Komati, Louis Leblanc, Wael Maharsy, Amarender Manchoju, Ryan Simard, Guillaume Tambutet, Claudia Teran, Starr Dostie, Michel Prévost, Mona Nemer* and Yvan Guindon*,

引用次数: 0

Abstract

A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in KRAS-mutated pancreatic human cancer cell lines, which exhibit partial resistance to gemcitabine, a widely used anticancer drug. LCB-2151 disrupts the two primary sources of ATP production, namely, glycolysis and mitochondrial oxidative phosphorylation, reducing the bioenergetic capacity of these cells and inducing the formation of reactive oxygen species. Metabolomics and mitochondrial respiration analyses reveal that LCB-2151 inhibits key enzymes in glycolysis, the TCA cycle, and fatty acid β-oxidation. These findings highlight a coordinated mechanism driving bioenergetic disruption and cell death.

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一种核苷类似物，具有C3 ' -立体全碳四元中心作为kras突变胰腺癌细胞的生物能量干扰物

一种新的核苷类似物LCB-2151已被开发出来，可诱导kras突变的人类胰腺癌细胞系细胞死亡，这些细胞系对广泛使用的抗癌药物吉西他滨（gemcitabine）表现出部分耐药性。LCB-2151破坏ATP产生的两个主要来源，即糖酵解和线粒体氧化磷酸化，降低这些细胞的生物能量能力并诱导活性氧的形成。代谢组学和线粒体呼吸分析显示LCB-2151抑制糖酵解、TCA循环和脂肪酸β-氧化的关键酶。这些发现强调了驱动生物能量破坏和细胞死亡的协调机制。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.