Exth-07. Design and Evaluation of Wp1122, an Inhibitor of Glycolysis With Increased CNS Uptake.

Priebe, Waldemar; Zieliński, Rafał; Fokt, Izabela; Felix, Edward; Venugopal, R.; Jayakumar, Arumugam; Khuong, Matthew; Krasiński, Maciej; Skóra, Stanisław

doi:10.1093/neuonc/noy148.356

Cited by 14 publications

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“…A highly promising novel group of compounds, the acetyl 2-DG analogs, have been developed in Dr. Waldemar Priebe's laboratory. Among the tested derivatives, lead compound WP1122 (3,6-di-O-acetyl-2-deoxy-D-glucose) has been selected for further studies [124] (Figure 9). It was confirmed that 2-FM, similarly to 2-DG, competes with mannose for N-linked protein glycosylation [121][122][123].…”

Section: Acetates Of 2-deoxy Monosaccharides As Prodrugsmentioning

confidence: 99%

“…A highly promising novel group of compounds, the acetyl 2-DG analogs, have been developed in Dr. Waldemar Priebe's laboratory. Among the tested derivatives, lead compound WP1122 (3,6-di-O-acetyl-2-deoxy-d-glucose) has been selected for further studies [124] (Figure 9). WP1122 enters cells and, importantly, crosses the BBB by passive diffusion rather than relying upon a specific glucose transporter.…”

Section: Acetates Of 2-deoxy Monosaccharides As Prodrugsmentioning

confidence: 99%

“…Importantly, most of their mechanisms of action, many of which could have useful applications in anticancer therapy, have been described. Clinical trials of 2-DG have demonstrated the challenges in its use in monotherapy due to poor drug-like characteristics [124], leading researchers to focus on improving bioavailability and achieving higher therapeutic concentrations. Novel 2-DG analogs such as WP1122 and others have renewed the old concept of glycolysis inhibition as an effective anticancer strategy.…”

Section: Perspectivesmentioning

confidence: 99%

“…It undergoes deacetylation by intracellular esterases, and is thereafter trapped inside the cell after phosphorylation at the C-6 hydroxyl group. The resultant 6-phospho-2-deoxyglucose acts as a competitive inhibitor of HK, blocking phosphorylation of d-glucose, and thereby inhibiting the glycolytic pathway [124]. The ability of WP1122 to target brain tissue makes it a serious candidate for the treatment of brain tumors, including GBM.…”

Section: Conflicts Of Interestmentioning

confidence: 99%

“…It has been shown that whereas 2-DG is rapidly metabolized, the prodrug WP1122 releases 2-DG, increasing its half-life and increasing therapeutic effect. WP1122 demonstrates good oral bioavailability, resulting in a two-fold higher plasma concentration of 2-DG than that achieved via administration of 2-DG alone [124]. In vitro experiments confirm that WP1122 potently inhibits glycolysis in U87 cell lines as determined by real-time monitoring of the extracellular acidification rate (ECAR), resulting in 2-10 times more potent anticancer activity when compared to 2-DG (half maximal inhibitory concentration (IC 50 ) range of 1-10 mM) in both hypoxic and normoxic conditions [124].…”

Section: Conflicts Of Interestmentioning

confidence: 99%

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2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Pająk

Siwiak

Sołtyka

et al. 2019

IJMS

373

267

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The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.using gluconeogenesis [5]. The hydrophilic nature of glucose requires specific glucose transporter proteins (GLUTs) to facilitate cellular uptake [6]. Higher glucose utilization by tumor cells requires overexpression of GLUT transporters to increase glucose uptake over 20-30 fold as compared to normal cells [7,8].Once inside the cell, glucose enters a cycle of changes to release energy in the form of ATP. Normal cells with access to oxygen utilize glycolysis to metabolize glucose into two molecules of pyruvate and form two molecules of ATP. The pyruvate is further oxidized in the mitochondria to acetyl-CoA via the pyruvate dehydrogenase complex. Acetyl-CoA then enters the Krebs cycle, in which it is oxidized into 2 molecules of CO 2 . The electrons derived from this process are used to create three molecules of NADH and one molecule of FADH 2 . These electron carrier molecules are reoxidized through the oxidoreductive systems of the respiratory chain, which drives ATP formation from ADP and inorganic phosphate (P i ) [9]. As a result of oxidative phosphorylation, 30 ATP molecules are generated from one molecule of glucose versus a net of 2 from glycolysis [9,10]. Oxygen is vitally important for this process as the final electron acceptor, allowing complete oxidation of glucose. In the case of insufficient oxygen concentrations, for example in skeletal muscle during periods of intense exertion, cells fall back on glycolysis, an ancient metabolic pathway evolved before the accumulation of significant atmospheric oxygen. Pyruvate, the end product of glycolysis, is reduced to lactate via lactic acid fermentation, cycling NADH back to NAD + [11]. The comparison of glucose metabolic pathways is presented in Figure 1.

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Section: Acetates Of 2-deoxy Monosaccharides As Prodrugsmentioning

confidence: 99%

“…A highly promising novel group of compounds, the acetyl 2-DG analogs, have been developed in Dr. Waldemar Priebe's laboratory. Among the tested derivatives, lead compound WP1122 (3,6-di-O-acetyl-2-deoxy-d-glucose) has been selected for further studies [124] (Figure 9). WP1122 enters cells and, importantly, crosses the BBB by passive diffusion rather than relying upon a specific glucose transporter.…”

Section: Acetates Of 2-deoxy Monosaccharides As Prodrugsmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Conflicts Of Interestmentioning

confidence: 99%

Section: Conflicts Of Interestmentioning

confidence: 99%

See 3 more Smart Citations

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Pająk

Siwiak

Sołtyka

et al. 2019

IJMS

373

267

View full text Add to dashboard Cite

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Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy

et al. 2022

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Background Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone‐sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate‐resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment. Methods A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4‐2 and DU145. Results Mass spectrometry analysis of LNCaP pre‐ and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2‐Deoxy‐ d‐glucose(2‐DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2‐DG results in synergistic cell death, a result not seen with simultaneous administration. Conclusions Hormone‐sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2‐DG) as a sequential treatment after ADT may be promising.

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Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms

Laussel

Léon

2020

Biochemical Pharmacology

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Exth-07. Design and Evaluation of Wp1122, an Inhibitor of Glycolysis With Increased CNS Uptake.

Cited by 14 publications

References 0 publications

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy

Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms

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