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

A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in <i>KRAS</i>-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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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-08-12
DOI
https://doi.org/10.1021/acsmedchemlett.5c00378
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Mona Nemer, Laura Collins, Guillaume Tambutet, Louis Leblanc et al.
1 links
ACS Medicinal Chemistry Letters
Cancer, Hypoxia, and Metabolism
article

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

Mona Nemer, Laura Collins, Guillaume Tambutet, Louis Leblanc, Janie Beauregard, Michel Prévost, Wael Maharsy, Michael Truong, Starr Dostie, Yvan Guindon, Ryan D. Simard, Amarender Manchoju, Philippe Mochirian, Georges N. Kanaan, Claudia Terán, Houda N. Tantawi, Hiba Komati
article en

Abstract

A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in <i>KRAS</i>-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.

ACS Medicinal Chemistry LettersVol. 16(9)
University of Ottawa (CA), Bipar (FR), Laboratoire de Chimie (FR), Montreal Clinical Research Institute (CA), Université de Montréal (CA)
Terry Fox Research Institute, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Canadian Glycomics Network
Openalex Percentile: Top 74%
Cancer, Hypoxia, and Metabolism
DOIOpen Access PDFOpenAlex
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