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. 2025 Aug 12;16(9):1814–1824. doi: 10.1021/acsmedchemlett.5c00378

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

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 §,*, Yvan Guindon †,‡,§,*
PMCID: PMC12434539  PMID: 40959263

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.

Keywords: Pancreatic ductal adenocarcinoma, nucleoside analogues, stereogenic all-carbon quaternary center, KRAS

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Despite significant advancements in cancer research, the outlook for many cancer patients remains poor, and treatment options are often limited. Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas, accounting for approximately 90% of all pancreatic malignancies. It is the sixth leading cause of cancer-related deaths worldwide and the third in the United States, with a five-year survival rate of 9% and a one-year survival rate of 24%. − PDAC is projected to become the second leading cause of cancer mortality in the US by 2030, surpassing breast and colorectal cancer. This poor prognosis is mainly due to the lack of early diagnostic methods and effective therapeutics. , Tumor resection and treatment with gemcitabine (Gem) and folfirinox (fluorouracil, leucovorin, irinotecan and oxaliplatin) are the current clinical gold standard treatments. ,

KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) is recognized as the key driver of pancreatic cancer. Unfortunately, treating these cancer types with gemcitabine, a nucleoside analogue, shows only limited in vitro and in vivo effectiveness against KRAS-activated mutations. Pancreatic cancer cell lines with KRAS-mutations, such as Panc-1 and Capan-2, exhibit partial resistance to gemcitabine in contrast to the wild-type pancreatic cell line BxPC3. , When mutated, KRAS remains persistently bound to GTP, keeping it constitutively active regardless of extracellular stimuli. Given that GTP is present in millimolar intracellular concentrations and binds to KRAS with picomolar affinity, direct inhibition of KRAS is challenging. Nonetheless, advances in directly targeting KRAS have emerged, especially for KRAS-G12C. , Covalent inhibitors against KRAS-G12C, namely sotorasib and adagrasib, have shown promising results in clinical trials and have recently received FDA approval for treating KRAS-G12C mutant nonsmall cell lung cancer. ,, These studies represent a breakthrough in KRAS-targeted therapy, although drug resistance remains a challenge. , Despite this progress in targeting KRAS, the G12C mutation occurs in only 1% of PDAC cases, , limiting its effectiveness for treating this disease. KRAS-G12D is the most common mutation in PDAC, occurring in 41% of cases. A recently identified small-molecule inhibitor, MRTX-1133, targeting KRAS-G12D has been tested in preclinical PDAC models, showing promising results. , In addition to mutation-specific inhibitors, pan-KRAS inhibitors capable of targeting the full spectrum of KRAS mutations have been developed. , Despite the potential therapeutic activity of these molecules, understanding their resistance profiles and toxicities, both alone and in combination with other drugs, remains an area of intense research. Many efforts have also focused on inhibiting the downstream effectors of KRAS. The RAF-MEK-ERK signaling pathway is notably involved in pancreatic carcinogenesis, although inhibition of this axis has, to date, not resulted in any clinical benefits. ,

It is well-established that cellular metabolism is altered in rapidly dividing cells, where glucose is consumed at elevated rates generating the majority of ATP outside the mitochondria (Warburg effect), leading to modifications in the function of the TCA cycle. The conversion of α-ketoglutarate to succinyl-CoA by the α-ketoglutarate dehydrogenase complex (α-KGDC) becomes the rate-limiting step in the TCA cycle, with glutamine serving as the primary substrate for the cycle after undergoing successive transformations into glutamate and α-ketoglutarate. KRAS mutations significantly impact glucose metabolism, contributing to metabolic reprogramming. Several enzymes in the glycolysis pathway, including hexokinase 2 (HK2), phosphofructokinase (PFK), and glucose transporter (GLUT1), are upregulated. As a result, the two primary sources of bioenergetics, glycolysis and the TCA cycle, are significantly altered in KRAS-mutated cancer cells.

CPI-613 (devimistat), a lipoic acid analogue, targets, albeit at very high doses, two major mitochondrial enzyme complexes that require lipoic acid as a cofactor: α-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH). Inhibiting both KGDH and PDH disrupts mitochondrial carbon metabolism and oxidative phosphorylation (OXPHOS), which depend on TCA cycle intermediates. − This deregulation of mitochondrial metabolism is the primary mechanism of CPI-613’s anticancer effect. In phase I and II clinical trials for PDAC and acute myeloid leukemia (AML), CPI-613 demonstrated a significant therapeutic index, prompting phase III trials. While mitochondrial targeting is central to CPI-613’s activity, PDAC also relies heavily on glycolysis for energy production. Consequently, combination regimens are explored to simultaneously disrupt multiple cancer hallmarks and enhance therapeutic outcomes. However, the results of some of these clinical trials have been disappointing.

To address the limitations of existing treatments for PDAC, we present a novel family of nucleoside analogues (NAs) featuring a lipoate chain, designed to enhance cytostatic activity against KRAS-mutated pancreatic cancer cell lines. Our laboratory has developed nucleoside analogues with a stereogenic all-carbon quaternary center at either the C2’ or C3′ position of the furanoside ring. , We hypothesize that these chiral centers enhance target specificity by inducing steric constraints and conformational bias, which may influence the binding to enzymes or receptors. Natural nucleosides can adopt diverse conformations ranging between north (C3′-endo) and south (C2’-endo). The presence of a quaternary center at C2’ is expected to favor the north (C3′-endo) conformation, while a quaternary center at C3′ may result in a distribution of north (C3′-endo) and south (C2’-endo) conformers. Triphosphate adenosine analogues bearing a C2’ stereogenic quaternary center were recently shown to be inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase. The potential of C3′ analogues as DNA chain terminators, similar to gemcitabine, needs to be evaluated.

As a class of pharmacological compounds, NAs encounter several challenges, including their cellular uptake, and subsequent activation by kinases into their mono-, di-, and triphosphates (Figure a). The downregulation of such enzymes and/or transporters is a key source of resistance in many cancers. In addition, NAs containing a cytosine nucleobase can be deaminated by cytidine deaminase (CDA) in the plasma or cellular media. Cell permeable, lipophilic C5′ phosphoramidate prodrugs, designed as masked monophosphates, have been successfully applied to the nucleoside antiviral agents sofosbuvir and remdesivir. Such prodrugs are designed to overcome both cellular uptake and the rate-limiting monophosphorylation (Figure b). An alternative approach involves linking a lipophilic entity to the N4-amine of the nucleobase to facilitate diffusion across the cell membrane and to temporally protect from deamination.

1.

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Mechanism of action of NAs and design of novel analogues. To act as antimetabolites, NAs enter the cell through diffusion or with transporters. The first rate-limiting phosphorylation by dCK is followed by a second and third phosphorylation. (a) Resistance pathways result from a decrease and/or increase in various key enzymes and degradation pathways (deamination by CDA, nucleobase cleavage, downregulation of active transport). (b) The resistance pathways (dCK or CDA) are overcome through installation of a phosphoramidate moiety (monophosphate prodrug) or a lipoate moiety attached to the N4-cytosine position. (c) Design of a novel lipoate chain to prevent β- and para-benzylic oxidation. (d) Novel nucleoside analogue scaffolds. CDA: cytidine deaminase, dCK: deoxycytidine kinase, hCNT: human concentrative nucleoside transporters; hENT: human equilibrative nucleoside transporters.

To evaluate this latter hypothesis, we developed a novel lipoate scaffold inspired by fatty acid-like compounds, such as CPI-613 (Figure c). Modifications included introducing a gem-dimethyl group to prevent β-oxidation and trifluoromethyl substituents to block phenolic derivative formation. These changes resulted in our novel lipoate moiety, 5 (Figure d). C3′-quaternary nucleoside analogues with and without a C5′ phosphoramidate, incorporating the lipoate moiety on the amine, were synthesized and their cytostatic activity was evaluated in vitro against pancreatic cancer cell lines. Among these, LCB-2151 (compound 2), featuring a gem-difluoride at the C2’ position, demonstrated promising activity.

Synthesis of Novel Nucleoside Analogue

Synthesis of the novel nucleoside analogue bearing the C5′-phosphoramidate began from a Mukaiyama aldolization between aldehyde 6 and enoxysilane 7 to form the silicon tethered radical precursors 8a,b (Scheme ). A highly diastereoselective (>20:1) intramolecular free radical-based allylation reaction was used to create the all-carbon stereogenic quaternary center providing methyl ester 9. It was demonstrated that this quaternary center could be embedded at C3′ of a nucleoside. However, an improved synthesis was required to differentiate the two primary hydroxyl groups at C3′ and C5′ to selectively incorporate a C5′ phosphoramidate. Silylation of the secondary alcohol of 9, and reduction of the ester with DIBAL-H provided primary alcohol 10 in excellent yield. Subsequent protection of the primary alcohol with a carboxybenzyl group followed by cleavage of the acetonide and oxidation using periodic acid resulted in the corresponding aldehyde that was immediately reduced to primary alcohol 11 in 86% yield for the three steps. The primary alcohol was protected with a triphenylmethyl (trityl) group followed by ozonolysis of the terminal alkene resulting in aldehyde 12. For this family of nucleoside analogues, a gem-difluoro group was incorporated at the C2’ position mimicking gemcitabine. Fluorination through in situ formation of the corresponding enamine with dl-proline and reaction with an electrophilic source of fluorine (NFSI) resulted in the difluoro aldehyde. Subsequent lactonization from TBAF desilylation of the secondary TBS protecting group provided lactols 13a,b. Iodofuranosides 14a,b were formed from activation of the anomeric position using Mitsunobu conditions (PPh3, I2) with a 1:5 ratio in favor of the α-anomer. N-glycosylation of 14a,b using silylated cytosine and AgBF4 in nitromethane at 60 °C resulted in a 5:1 mixture of nucleosides 15a,b in favor of the desired β-anomer with a 61% yield. Nucleobase addition is seemingly proceeding through an SN2 mechanism with slow anomerization between iodides 14a and 14b. Gratifyingly, these conditions provided an improved selectivity for the desired β-nucleoside as compared to the 1:1.5 (β:α) ratio that we previously reported with TMSOTf activation of an anomeric tosylate bearing C3′ and C5′-benzoate protecting groups. Cleavage of the C5′-trityl using 10% TFA, incorporation of the S p phosphoramidate and hydrogenation to remove the C3′ Cbz provided 3.

1. Synthesis of C5′-Phosphoramidate Nucleoside Analogue 3 .

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Synthesis of Octanoic Derivatives

Synthesis of our novel octanoic acid derivative, 5, started from D-malic acid which was first reduced to the corresponding triol (Scheme ). A 1,3-diol protection provided benzylidene acetal 16 in 58% yield over two steps. Swern oxidation of the primary alcohol followed by a Wittig–Horner reaction provided the α,β-unsaturated ketone 17 in 59% yield. After hydrogenation of the double bond, a second Wittig–Horner reaction resulted in a 2:1 E/Z mixture of α,β-unsaturated esters 18a,b. Diol 19 was formed from conjugate addition using Gilman reagents generating the gem-dimethyl moiety followed by acidic cleavage of the benzylidene. Displacement of the C6 and C8 mesylate leaving groups with para-CF3 benzenemethanethiol provided the corresponding thioether. Carboxylic acid 5 was generated in 79% yield after a final saponification. Amide coupling of the β-gem-dimethyl octanoic acid derivative 5 with the previously reported parent nucleoside scaffold 1 provided LCB-2151 (compound 2) in a 70% isolated yield. Using the same amide coupling of lipoate 5 and the nucleoside already bearing the C5′-phosphoramidate 3, provided analogue 4.

2. Synthesis of Octanoic Acid Derivative 5 and Nucleoside Analogues LCB-2151 (Compound 2) and 4 .

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In Vitro Evaluation

Gemcitabine demonstrated only modest activity against the two pancreatic KRAS-mutated cell lines tested, Panc-1 and Capan-2 in contrast to non-KRAS mutated cell lines HepG2 (hepatocellular carcinoma (HCC)) and BxPC3 (PDAC) (Figure ). Our nucleoside analogue, 1, which differs from Gem by having a C3′ stereogenic quaternary carbon bearing a hydroxymethyl group, did not show significant activity in the same cell lines as was also the case for the C5′-phosphoramidate analogue, 3. Interestingly, at 80 μM, the β-gem-dimethyl octanoic acid derivative, 5, induced 40% Panc-1 cell death after 96 h, while CPI-613 was inactive at this concentration. Contrary to gemcitabine, LCB-2151, bearing the lipoate moiety, demonstrated remarkable activity against all four cell lines, achieving 100% cell death. LCB-2151 showed a significant dose-dependent decrease in cellular viability with an IC50 ranging between 8 and 17 μM against the various cell lines. The corresponding phosphoramidate prodrug, 4, did not show enhanced activity. Importantly, cleavage of LCB-2151 to the lipoate 5 and the parent nucleoside 1 was not observed in vitro or in vivo.

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In vitro evaluation of octanoic acid derivatives and novel NAs in four human cancer cell lines. Four human cancer cell lines, Panc-1 (PDAC, KRAS-G12D mutation), Capan-2 (PDAC, KRAS-G12 V mutation), HepG2 (HCC), and BxPC3 (PDAC, wild-type KRAS), were treated with varying concentrations of gemcitabine, CPI-613, or the novel analogues for 96 h. Cell viability was then measured using the CellTiter-Glo assay. Results were obtained from at least 3 independent experiments (n = 3) in triplicate. Preliminary results obtained for CPI-613 (HepG2: n = 1 in triplicate, and BxPC3: n = 2 in triplicate), compound 1 (Capan-2 and HepG2: n = 1 in duplicate), compound 4 (n = 2 in triplicate), and compound 3 (n = 1 in duplicate) are also shown. Data are presented as mean ± SEM

Interestingly, Panc-1 cells that were treated with gemcitabine were responsive to subsequent treatment with LCB-2151 (Figure a and b). Cells that survived a first exposure to gemcitabine were retreated with our molecule alone or in combination with Gem. While retreatment with Gem showed some cell death, LCB-2151 demonstrated significantly higher cytotoxicity at both 48- and 96-h time points. The lead molecule significantly increased cell death, with no enhancement observed when cotreated with Gem.

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Treatment of gemcitabine-resistant Panc-1 cells with 2 (LCB-2151). Panc-1 cells were treated with 20 μM of gemcitabine for 96 h. Remaining cells were seeded at 10,000 cells per well in a 96-well plate. Next day, cells were treated with vehicle control (DMSO), 20 μM gemcitabine, 20 μM of 2 (LCB-2151), or a combination of 20 μM gemcitabine and 20 μM of 2 (LCB-2151). Cell viability was measured using CellTiter-Glo after (a) 48 h or (b) 96 h. N = 3. Data are presented as mean ± SEM ns, not significant, *p ≤ 0.05, ****p ≤ 0.0001.

Mechanism of Action

Interference of lead compound LCB-2151 with the TCA cycle, the suggested mode of action of CPI-613, was verified through a targeted metabolomics study (Figure a). The first interesting observation was that the level of acetyl-CoA was not significantly altered. This suggests that the pyruvate dehydrogenase complex is not inhibited, contrary to CPI-613. Mitochondrial α-ketoglutarate dehydrogenase (KGDH) was affected as evidenced by the significant decrease in both succinyl CoA and succinate. Major effects on the glycolytic pathway were also observed. An apparent inhibition of the reaction catalyzed by cytoplasmic phosphofructokinase-1 (PFK-1), the rate limiting step of glycolysis, was observed as seen by the increase in fructose-6-phosphate and decrease in the fructose-1,6-bisphosphate product. This could be underestimated since a mixture of glucose bisP/fructose bisP (FBP) is reported. Pyruvate was also reduced, consistent with the decrease in FBP. Importantly, the levels of NAD+ and NADH were also significantly decreased, suggesting that the redox capacity of the cell is reduced. Based on these results, LCB-2151 seemingly inhibits both KGDH in the mitochondria and PFK, the rate-limiting step of glycolysis in the cytoplasm as illustrated in Figure c. Taking into consideration that LCB-2151 contains a β-gem-dimethyl octanoic moiety, it was hypothesized that fatty-acid oxidation may also be affected. LCB-2151 causes a statistically significant decrease in the levels of several long-chain fatty acids whereas fatty acid-carnitine levels are elevated (Figure b). Fatty acids rely on an intricate transport system to enter the mitochondria to undergo β-oxidation. Acyl-CoAs must be transformed into acyl-carnitine esters by the outer mitochondrial membrane protein carnitine palmitoyl transferase 1 (CPT1) (Figure c). Once they have entered the mitochondria via CACT (carnitine acyl-carnitine translocase), CPT2, located in the inner mitochondrial membrane, regenerates acyl-CoA which is then processed by the β-oxidation cascade. These initial results suggest that LCB-2151 alters the amount of fatty acid acyl-CoAs available to undergo β-oxidation. As the total amount of acyl-carnitine was measured, it is uncertain if the accumulation of acyl-carnitine is mainly in the cytoplasm or in the mitochondria, thus, either CACT and/or CPT2 may be inhibited by LCB-2151 (Figure c).

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LCB-2151 targets glycolysis, the TCA cycle, and fatty-acid metabolism. Panc-1 cells were treated with 20 μM of compound 2 (LCB-2151) or vehicle control (DMSO) for 6 h. Fifty metabolites in five central carbon metabolism pathways were measured by HPLC-MS/MS (Creative Proteomics). Metabolite analysis was an average of 5 replicates for each treatment. Fold-change was calculated between vehicle and LCB-2151 treated sample. p ≤ 0.05 was considered significant. (a) represents the Central Carbon Metabolism (CCM) metabolites while (b) represents the Fatty-Acid and Acyl-Carnitine Analysis. (c) Proposed mechanism of action of compound 2 (LCB-2151).

Disruption of the fatty acid β-oxidation pathway combined with the decreased levels of NAD+ and NADH led us to hypothesize that the level of reactive oxygen species (ROS) might be increased. Using the MitoSOX assay, a significant increase in ROS levels in LCB-2151 treated cells compared to DMSO-treated cells was noted (Figure ).

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LCB-2151 enhances mitochondrial ROS. Panc-1 cells were treated with 20 μM of compound 2 (LCB-2151) or vehicle control (DMSO) for 6 h, or with 20 μM H2O2 (positive control) for 2 h. Mitochondrial ROS levels were detected using MitoSOX Red staining. (a) representative figures and (b) corresponding violin plot. N = 3. ****p ≤ 0.0001.

LCB-2151 Interferes with Mitochondrial Cell Respiration

The impact of LCB-2151 on the TCA cycle and fatty acid metabolism, both of which occur in the mitochondria, prompted us to investigate its effects on mitochondrial respiration using the Seahorse XF96 Extracellular Flux Analyzer (Figure ). Panc-1 cells treated with LCB-2151 showed a significant decrease in basal respiration, ATP-linked respiration, maximal respiration, and spare capacity compared to DMSO-treated cells as determined by the oxygen consumption rate (OCR) levels (Figure a, c-g). This indicates an impaired function of the electron transport chain (ETC), responsible for mitochondrial respiration, which can be caused by a direct inhibition of ETC proteins or a lack of substrates (NADH or succinate) needed for the activity of complex I (CI) and complex II (CII), respectively. The extracellular acidification rate (ECAR) measured in this assay, reflecting glycolysis, demonstrated a higher glycolytic rate in LCB-2151-treated Panc-1 cells at the baseline level compared to DMSO-treated cells. However, upon the addition of monensin, which maximizes glycolysis, LCB-2151-treated cells showed an impaired glycolytic capacity represented by lower maximal ECAR compared to their DMSO-treated counterpart (Figure b,h). No such effects were observed in the Gem-treated cells. To investigate whether LCB-2151 carries out its effects on mitochondrial respiration by directly targeting ETC proteins, acute treatment with LCB-2151 was performed. Administration of FCCP followed by LCB-2151 addition was also tested to maximize mitochondrial respiration before treatment. The results indicated that LCB-2151 had no immediate impact on mitochondrial respiration, suggesting that it does not directly influence the activity of ETC proteins (Figure S1). The protein level of the different ETC complexes was also measured, yet no significant changes were observed (Figure S2).

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LCB-2151 impairs mitochondrial respiration and glycolysis in Panc-1 cells. Oxygen consumption rate (OCR) and Extracellular Acidification Rate (ECAR), represented in (a) and (b), respectively, in Panc-1 cells were measured using Seahorse XF96 Extracellular Flux Analyzer. Panc-1 cells were treated with 20 μM of LCB-2151 (compound 2), 20 μM gemcitabine, or vehicle control (DMSO) for 6 h, or were left untreated. Three baseline measurements were taken before sequential administration of oligomycin (1 μM), FCCP (carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone) (0.5 μM), a combination of rotenone and antimycin A (A.A) (at 0.5 μM each), and monensin (20 μM). (c-h) Bar graphs representing mitochondrial respiration parameters. Experiment performed in triplicate (n = 3) with a total of 64–72 wells per treatment condition. Data are presented as mean ± SEM ns, not significant; *p ≤ 0.05; **p ≤ 0.001; ****p ≤ 0.00001.

Collectively, this data demonstrates that LCB-2151 has a significant effect on mitochondrial health and function in Panc-1 cells. A major metabolic disruption occurs due to a dysfunctional ETC, potentially from a lack of essential substrates such as succinate and NADH. The reduction in pyruvate observed in the metabolomics study (Figure a), demonstrates that the glycolytic capacity is also diminished. This raises the question of how to reconcile the potential inhibition of KGDH, PFK, and CPT2/CACT by our novel nucleoside analogue. We propose the following mechanistic scenario. ATP production by the mitochondrial ETC relies on a coordinated series of redox reactions. The TCA cycle supplies succinate to Complex II and concurrently generates ROS. One key TCA enzyme, KGDH, is particularly vulnerable to ROS-induced oxidative damage, which can impair its activity. Mitochondrial respiratory homeostasis is supported by the β-oxidation of acyl-CoAs, which generates NADH and FADH2-both essential substrates for the ETC. Furthermore, the NAD+/NADH redox couple plays a crucial role in scavenging mitochondrial ROS and preserving KGDH activity, thereby sustaining the function of the TCA cycle. This well coordinated sequence of metabolic events is disrupted by LCB-2151, which impairs β-oxidation by inhibiting either the transport of acyl-carnitines (CACT) or their conversion (CPT2) to acyl-CoAs - key substrates required for the β-oxidation pathway. As a result, mitochondrial ATP production is ultimately suppressed. Inhibition of fatty acid transport may also lead to the accumulation of acyl-CoAs in the cytoplasm (Figure c). Notably, palmitoyl-CoA is a known inhibitor of PFK, which can further impair the cell’s glycolytic capacity to generate ATP.

From the outset of this research program, our goal was to discover a novel nucleoside analogue for treating KRAS-mutated pancreatic cancers, which currently have limited therapeutic options. We hypothesized that introducing a quaternary stereogenic center at C3′ of the furanoside ring would induce selectivity, while a gem-difluoride at C2’ would enhance activity. Concurrently, a novel lipoate analogue, designed to resist β-oxidation and oxidation para to the benzylthiol moieties, demonstrated greater potency than CPI-613 against the Panc-1 cell line, achieving a maximum inhibition of 40%. By combining these two chemical entities through an amide linkage at N4 of the cytosine nucleobase, a lead molecule, LCB-2151 (compound 2), was developed which induced cell death with 100% efficacy and an IC50 of 8–17 μM for the various cancer cell lines tested including the ones bearing KRAS mutations. The unique profile of this molecule, compared to gemcitabine, highlights the mechanistic differences between these two nucleoside analogues. Importantly, LCB-2151 induced significant cytotoxicity to Panc-1 cells that survived a first gemcitabine treatment.

Metabolomic studies revealed a disruption of both ATP production pathways: first, by inhibiting PFK, the rate-determining enzyme of glycolysis; and second, by disrupting the mitochondrial TCA cycle through inhibition of KGDH and inhibition of fatty acid β-oxidation, resulting from interference with the carnitine transport enzymes CACT or CPT2. This dual interference in ATP production led to a collapse of cellular respiration, as demonstrated by Seahorse analyses, and increased ROS production. Targeting multiple energy-producing pathways may reduce the likelihood of resistance to this lead compound. Additionally, its potential to enhance the anticancer efficacy of existing pharmacological agents, such as being an adjuvant to gemcitabine, is promising. LCB-2151 also has the capacity to potentiate radiation therapy, which relies on ROS production. Our mechanistic hypothesis will be further investigated by directly inhibiting these enzymes individually through biochemical assays with our lead molecule in addition to genetic manipulations. In parallel, unbiased mechanistic studies using photoaffinity probes are currently in progress. Ongoing in vivo experiments to evaluate the potential of LCB-2151 as an antitumor agent are also underway.

Safety Statement

No unexpected or unusually high safety hazards were encountered.

Supplementary Material

ml5c00378_si_001.pdf (5.6MB, pdf)

Acknowledgments

Funding for this research has been granted from the Natural Sciences and Engineering Research Council (NSERC, #06507), the Canadian Institutes of Health Research (CIHR, #145885), the Canadian Glycomics Network (#CD-31), and the Terry Fox Research Institute (#2010-35). The authors acknowledge the Cell Biology and Image Acquisition Core (RRID: SCR_021845) funded by the University of Ottawa, Ottawa, Natural Sciences and engineering Research Council of Canada, and the Canada Foundation for Innovation. BioRender was used to generate the illustration in Figure 4c.

Glossary

Abbreviations

CDA

Cytidine deaminase

CACT

Carnitine acyl-carnitine translocase

CPT

Carnitine palmitoyl transferase

dCK

deoxycytidine kinase

ECAR

Extracellular acidification rate

ETC

Electron transport chain

Gem

Gemcitabine

HCC

Hepatocellular carcinoma

KGDH

Ketoglutarate dehydrogenase

KRAS

Kirsten rat sarcoma 2 viral oncogene homologue

NAs

Nucleoside analogues

PDAC

Pancreatic ductal adenocarcinoma

PFK

Phosphofructokinase-1

OCR

Oxygen consumption rate

ROS

Reactive Oxygen Species

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00378.

  • Biology assays and protocols, general comments for compound synthesis, experimental procedures, compound characterizations, 1H NMR and 13C NMR spectra for all new compounds, and HPLC-UV chromatograms are provided (PDF)

The authors declare no competing financial interest.

References

  1. Dreyer S. B., Beer P., Hingorani S. R., Biankin A. V.. Improving outcomes of patients with pancreatic cancer. Nat. Rev. Clin Oncol. 2025;22(6):439–456. doi: 10.1038/s41571-025-01019-9. [DOI] [PubMed] [Google Scholar]
  2. Bray F., Laversanne M., Sung H., Ferlay J., Siegel R. L., Soerjomataram I., Jemal A.. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
  3. Rahib L., Wehner M. R., Matrisian L. M., Nead K. T.. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708. doi: 10.1001/jamanetworkopen.2021.4708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ushio J., Kanno A., Ikeda E., Ando K., Nagai H., Miwata T., Kawasaki Y., Tada Y., Yokoyama K., Numao N., Tamada K., Lefor A. K., Yamamoto H.. Pancreatic Ductal Adenocarcinoma: Epidemiology and Risk Factors. Diagnostics (Basel) 2021;11(3):562. doi: 10.3390/diagnostics11030562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Siegel R. L., Miller K. D., Fuchs H. E., Jemal A.. Cancer statistics, 2022. CA Cancer J. Clin. 2022;72(1):7–33. doi: 10.3322/caac.21708. [DOI] [PubMed] [Google Scholar]
  6. Halbrook C. J., Lyssiotis C. A., Pasca di Magliano M., Maitra A.. Pancreatic cancer: Advances and challenges. Cell. 2023;186(8):1729–1754. doi: 10.1016/j.cell.2023.02.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Park W., Chawla A., O’Reilly E. M.. Pancreatic Cancer: A Review. JAMA. 2021;326(9):851–862. doi: 10.1001/jama.2021.13027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Singhi A. D., Wood L. D.. Early detection of pancreatic cancer using DNA-based molecular approaches. Nat. Rev. Gastroenterol Hepatol. 2021;18(7):457–468. doi: 10.1038/s41575-021-00470-0. [DOI] [PubMed] [Google Scholar]
  9. Leowattana W., Leowattana P., Leowattana T.. Systemic treatment for advanced pancreatic cancer. World J. Gastrointest Oncol. 2023;15(10):1691–1705. doi: 10.4251/wjgo.v15.i10.1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mosalem O. M., Abdelhakeem A., Abdel-Razeq N. H., Babiker H.. Pancreatic ductal adenocarcinoma (PDAC): clinical progress in the last five years. Expert Opin Investig Drugs. 2025;34(3):149–160. doi: 10.1080/13543784.2025.2473698. [DOI] [PubMed] [Google Scholar]
  11. Linehan A., O’Reilly M., McDermott R., O’Kane G. M.. Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies. Front Med. (Lausanne) 2024;11:1369136. doi: 10.3389/fmed.2024.1369136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Norton C., Shaw M. S., Rubnitz Z., Smith J., Soares H. P., Nevala-Plagemann C. D., Garrido-Laguna I., Florou V.. KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma. JAMA Netw Open. 2025;8(1):e2453588. doi: 10.1001/jamanetworkopen.2024.53588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huanwen W., Zhiyong L., Xiaohua S., Xinyu R., Kai W., Tonghua L.. Intrinsic chemoresistance to gemcitabine is associated with constitutive and laminin-induced phosphorylation of FAK in pancreatic cancer cell lines. Mol. Cancer. 2009;8:125. doi: 10.1186/1476-4598-8-125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Singhal A., Li B. T., O’Reilly E. M.. Targeting KRAS in cancer. Nat. Med. 2024;30(4):969–983. doi: 10.1038/s41591-024-02903-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Yang A., Li M., Fang M.. The Research Progress of Direct KRAS G12C Mutation Inhibitors. Pathol Oncol Res. 2021;27:631095. doi: 10.3389/pore.2021.631095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kim D., Xue J. Y., Lito P.. Targeting KRAS­(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients. Cell. 2020;183(4):850–859. doi: 10.1016/j.cell.2020.09.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ostrem J. M., Peters U., Sos M. L., Wells J. A., Shokat K. M.. K-Ras­(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51. doi: 10.1038/nature12796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Janne P. A., Sabari J. K., Spira A. I.. Adagrasib in Non-Small-Cell Lung Cancer. Reply. N Engl J. Med. 2022;387(13):1238–1239. doi: 10.1056/NEJMc2210539. [DOI] [PubMed] [Google Scholar]
  19. Hong D. S., Fakih M. G., Strickler J. H., Desai J., Durm G. A., Shapiro G. I., Falchook G. S., Price T. J., Sacher A., Denlinger C. S., Bang Y. J., Dy G. K., Krauss J. C., Kuboki Y., Kuo J. C., Coveler A. L., Park K., Kim T. W., Barlesi F., Munster P. N., Ramalingam S. S., Burns T. F., Meric-Bernstam F., Henary H., Ngang J., Ngarmchamnanrith G., Kim J., Houk B. E., Canon J., Lipford J. R., Friberg G., Lito P., Govindan R., Li B. T.. KRAS­(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J. Med. 2020;383(13):1207–1217. doi: 10.1056/NEJMoa1917239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Punekar S. R., Velcheti V., Neel B. G., Wong K. K.. The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin Oncol. 2022;19(10):637–655. doi: 10.1038/s41571-022-00671-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liu J., Kang R., Tang D.. The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther. 2022;29(7):875–878. doi: 10.1038/s41417-021-00383-9. [DOI] [PubMed] [Google Scholar]
  22. Waters A. M., Der C. J.. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 2018;8(9):a031435. doi: 10.1101/cshperspect.a031435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Strickler J. H., Satake H., George T. J., Yaeger R., Hollebecque A., Garrido-Laguna I., Schuler M., Burns T. F., Coveler A. L., Falchook G. S., Vincent M., Sunakawa Y., Dahan L., Bajor D., Rha S. Y., Lemech C., Juric D., Rehn M., Ngarmchamnanrith G., Jafarinasabian P., Tran Q., Hong D. S.. Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer. N Engl J. Med. 2023;388(1):33–43. doi: 10.1056/NEJMoa2208470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wang X., Allen S., Blake J. F., Bowcut V., Briere D. M., Calinisan A., Dahlke J. R., Fell J. B., Fischer J. P., Gunn R. J., Hallin J., Laguer J., Lawson J. D., Medwid J., Newhouse B., Nguyen P., O’Leary J. M., Olson P., Pajk S., Rahbaek L., Rodriguez M., Smith C. R., Tang T. P., Thomas N. C., Vanderpool D., Vigers G. P., Christensen J. G., Marx M. A.. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS­(G12D) Inhibitor. J. Med. Chem. 2022;65(4):3123–3133. doi: 10.1021/acs.jmedchem.1c01688. [DOI] [PubMed] [Google Scholar]
  25. Kemp S. B., Cheng N., Markosyan N., Sor R., Kim I. K., Hallin J., Shoush J., Quinones L., Brown N. V., Bassett J. B., Joshi N., Yuan S., Smith M., Vostrejs W. P., Perez-Vale K. Z., Kahn B., Mo F., Donahue T. R., Radu C. G., Clendenin C., Christensen J. G., Vonderheide R. H., Stanger B. Z.. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discov. 2023;13(2):298–311. doi: 10.1158/2159-8290.CD-22-1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hallin J., Bowcut V., Calinisan A., Briere D. M., Hargis L., Engstrom L. D., Laguer J., Medwid J., Vanderpool D., Lifset E., Trinh D., Hoffman N., Wang X., David Lawson J., Gunn R. J., Smith C. R., Thomas N. C., Martinson M., Bergstrom A., Sullivan F., Bouhana K., Winski S., He L., Fernandez-Banet J., Pavlicek A., Haling J. R., Rahbaek L., Marx M. A., Olson P., Christensen J. G.. Anti-tumor efficacy of a potent and selective non-covalent KRAS­(G12D) inhibitor. Nat. Med. 2022;28(10):2171–2182. doi: 10.1038/s41591-022-02007-7. [DOI] [PubMed] [Google Scholar]
  27. Kim D., Herdeis L., Rudolph D., Zhao Y., Bottcher J., Vides A., Ayala-Santos C. I., Pourfarjam Y., Cuevas-Navarro A., Xue J. Y., Mantoulidis A., Broker J., Wunberg T., Schaaf O., Popow J., Wolkerstorfer B., Kropatsch K. G., Qu R., de Stanchina E., Sang B., Li C., McConnell D. B., Kraut N., Lito P.. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature. 2023;619(7968):160–166. doi: 10.1038/s41586-023-06123-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Corcoran R. B.. A single inhibitor for all KRAS mutations. Nat. Cancer. 2023;4(8):1060–1062. doi: 10.1038/s43018-023-00615-x. [DOI] [PubMed] [Google Scholar]
  29. Adamopoulos C., Cave D. D., Papavassiliou A. G.. Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives. Int. J. Mol. Sci. 2024;25(3):1631. doi: 10.3390/ijms25031631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kinsey C. G., Camolotto S. A., Boespflug A. M., Guillen K. P., Foth M., Truong A., Schuman S. S., Shea J. E., Seipp M. T., Yap J. T., Burrell L. D., Lum D. H., Whisenant J. R., Gilcrease G. W. 3rd, Cavalieri C. C., Rehbein K. M., Cutler S. L., Affolter K. E., Welm A. L., Welm B. E., Scaife C. L., Snyder E. L., McMahon M.. Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 2019;25(4):620–627. doi: 10.1038/s41591-019-0367-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Bryant K. L., Stalnecker C. A., Zeitouni D., Klomp J. E., Peng S., Tikunov A. P., Gunda V., Pierobon M., Waters A. M., George S. D., Tomar G., Papke B., Hobbs G. A., Yan L., Hayes T. K., Diehl J. N., Goode G. D., Chaika N. V., Wang Y., Zhang G. F., Witkiewicz A. K., Knudsen E. S., Petricoin E. F. 3rd, Singh P. K., Macdonald J. M., Tran N. L., Lyssiotis C. A., Ying H., Kimmelman A. C., Cox A. D., Der C. J.. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 2019;25(4):628–640. doi: 10.1038/s41591-019-0368-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vander Heiden M. G., Cantley L. C., Thompson C. B.. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33. doi: 10.1126/science.1160809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Son J., Lyssiotis C. A., Ying H., Wang X., Hua S., Ligorio M., Perera R. M., Ferrone C. R., Mullarky E., Shyh-Chang N., Kang Y., Fleming J. B., Bardeesy N., Asara J. M., Haigis M. C., DePinho R. A., Cantley L. C., Kimmelman A. C.. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496(7443):101–5. doi: 10.1038/nature12040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vatrinet R., Leone G., De Luise M., Girolimetti G., Vidone M., Gasparre G., Porcelli A. M.. The alpha-ketoglutarate dehydrogenase complex in cancer metabolic plasticity. Cancer Metab. 2017;5(1):3. doi: 10.1186/s40170-017-0165-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Anderson M., Marayati R., Moffitt R., Yeh J. J.. Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. Oncotarget. 2017;8(34):56081–56094. doi: 10.18632/oncotarget.9760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Reddy V. B., Boteju L., Boteju A., Shen L., Kassahun K., Reddy N., Sheldon A., Luther S., Hu K.. Vitro and In Vivo Metabolism of a Novel Antimitochondrial Cancer Metabolism Agent, CPI-613, in Rat and Human. Drug Metab. Dispos. 2022;50(4):361–373. doi: 10.1124/dmd.121.000726. [DOI] [PubMed] [Google Scholar]
  37. Stuart S. D., Schauble A., Gupta S., Kennedy A. D., Keppler B. R., Bingham P. M., Zachar Z.. A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014;2(1):4. doi: 10.1186/2049-3002-2-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zachar Z., Marecek J., Maturo C., Gupta S., Stuart S. D., Howell K., Schauble A., Lem J., Piramzadian A., Karnik S., Lee K., Rodriguez R., Shorr R., Bingham P. M.. Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J. Mol. Med. (Berl) 2011;89(11):1137–48. doi: 10.1007/s00109-011-0785-8. [DOI] [PubMed] [Google Scholar]
  39. Neitzel C., Demuth P., Wittmann S., Fahrer J.. Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities. Cancers (Basel) 2020;12(7):1731. doi: 10.3390/cancers12071731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Anderson R. G., Ghiraldeli L. P., Pardee T. S.. Mitochondria in cancer metabolism, an organelle whose time has come? Biochim Biophys Acta Rev. Cancer. 2018;1870(1):96–102. doi: 10.1016/j.bbcan.2018.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Alistar A., Morris B. B., Desnoyer R., Klepin H. D., Hosseinzadeh K., Clark C., Cameron A., Leyendecker J., D’Agostino R. Jr., Topaloglu U., Boteju L. W., Boteju A. R., Shorr R., Zachar Z., Bingham P. M., Ahmed T., Crane S., Shah R., Migliano J. J., Pardee T. S., Miller L., Hawkins G., Jin G., Zhang W., Pasche B.. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017;18(6):770–778. doi: 10.1016/S1470-2045(17)30314-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Encarnacion-Rosado J., Kimmelman A. C.. Harnessing metabolic dependencies in pancreatic cancers. Nat. Rev. Gastroenterol Hepatol. 2021;18(7):482–492. doi: 10.1038/s41575-021-00431-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kumstel S., Schreiber T., Goldstein L., Stenzel J., Lindner T., Joksch M., Zhang X., Wendt E. H. U., Schonrogge M., Krause B., Vollmar B., Zechner D.. Targeting pancreatic cancer with combinatorial treatment of CPI-613 and inhibitors of lactate metabolism. PLoS One. 2022;17(4):e0266601. doi: 10.1371/journal.pone.0266601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Philip P. A., Sahai V., Bahary N., Mahipal A., Kasi A., Rocha Lima C. M. S., Alistar A. T., Oberstein P. E., Golan T., Metges J. P., Lacy J., Fountzilas C., Lopez C. D., Ducreux M., Hammel P., Salem M., Bajor D., Benson A. B., Luther S., Pardee T., Van Cutsem E.. Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study. J. Clin Oncol. 2024;42(31):3692–3701. doi: 10.1200/JCO.23.02659. [DOI] [PubMed] [Google Scholar]
  45. Guindon, Y. ; Mochirian, P. ; Nemer, M. . Nucleoside and Nucleotide Analogues Bearing a Quaternary All-Carbon Stereogenic Center at the 2’ Position and Methods of Use as a Cardioprotective Agent. PCT/CA2017/051095; International Publication WO2018/049534A1; European Patent EP3 512 860B1, 25 November 2020; U.S. Patent 11,434,255 B2, 06 September 2022.
  46. Guindon, Y. ; Mochirian, P. ; Nemer, M. ; Prévost, M. . Nucleoside Analogues and Methods of Use Thereof. PCT/CA2017/051096; International Publication WO2018/049535A1; U.S. Patent 11,453,695 B2, 27 September 2022.
  47. Salmaso V., Jacobson K. A.. Survey of ribose ring pucker of signaling nucleosides and nucleotides. Nucleosides Nucleotides Nucleic Acids. 2020;39(1–3):322–341. doi: 10.1080/15257770.2019.1658115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Manchoju A., Zelli R., Wang G., Eymard C., Oo A., Nemer M., Prevost M., Kim B., Guindon Y.. Nucleotide Analogues Bearing a C2’ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors. Molecules. 2022;27(2):564. doi: 10.3390/molecules27020564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Hruba L., Das V., Hajduch M., Dzubak P.. Nucleoside-based anticancer drugs: Mechanism of action and drug resistance. Biochem. Pharmacol. 2023;215:115741. doi: 10.1016/j.bcp.2023.115741. [DOI] [PubMed] [Google Scholar]
  50. Mehellou Y., Rattan H. S., Balzarini J.. The ProTide Prodrug Technology: From the Concept to the Clinic. J. Med. Chem. 2018;61(6):2211–2226. doi: 10.1021/acs.jmedchem.7b00734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kaliya K., Bhardwaj N., Ruchika, Saneja A.. Synthesis of a Gemcitabine Prodrug and its Encapsulation into Polymeric Nanoparticles for Improved Therapeutic Efficacy. ChemMedChem. 2025;20:e202400532. doi: 10.1002/cmdc.202400532. [DOI] [PubMed] [Google Scholar]
  52. Tambutet G., Becerril-Jimenez F., Dostie S., Simard R., Prevost M., Mochirian P., Guindon Y.. Dual-face nucleoside scaffold featuring a stereogenic all-carbon quaternary center. Intramolecular silicon tethered group-transfer reaction. Org. Lett. 2014;16(21):5698–701. doi: 10.1021/ol502777r. [DOI] [PubMed] [Google Scholar]
  53. Guerra I. M. S., Ferreira H. B., Melo T., Rocha H., Moreira S., Diogo L., Domingues M. R., Moreira A. S. P.. Mitochondrial Fatty Acid beta-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review. Int. J. Mol. Sci. 2022;23(22):13933. doi: 10.3390/ijms232213933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Jenkins C. M., Yang J., Sims H. F., Gross R. W.. Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. J. Biol. Chem. 2011;286(14):11937–50. doi: 10.1074/jbc.M110.203661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kim W., Lee S., Seo D., Kim D., Kim K., Kim E., Kang J., Seong K. M., Youn H., Youn B.. Cellular Stress Responses in Radiotherapy. Cells. 2019;8(9):1105. doi: 10.3390/cells8091105. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

ml5c00378_si_001.pdf (5.6MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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