Design, Synthesis, and Preliminary Biological Evaluation of GlcNAc‐6P Analogues for the Modulation of Phosphoacetylglucosamine Mutase 1 (AGM1/PGM3)

Paiotta, Alice; D’Orazio, Giuseppe; Palorini, Roberta; Ricciardiello, Francesca; Zoia, Luca; Votta, Giuseppina; Gioia, Luca De; Chiaradonna, Ferdinando; Ferla, Barbara La

doi:10.1002/ejoc.201800183

Cited by 10 publications

(13 citation statements)

References 26 publications

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“…To further detail the role of the KRAS status in the dependence of the PDAC cells on HBP and N -glycosylation processes, we took advantage of an HBP inhibitor previously generated by our group, named FR054 [ 13 ], which is able to inhibit the HBP enzyme PGM3 causing a reduction in the HBP flux and consequently a significant attenuation of both protein N - and O -glycosylations [ 14 , 15 ]. MIA PaCa-2, PANC-1 and BxPC-3 cell lines were treated for 48 h with different concentrations of FR054 and then the cell viability and death were quantified.…”

Section: Resultsmentioning

confidence: 99%

“…Oxamate, 2-deoxyglucose (2-DG), and mannose were purchased from Sigma-Aldrich (Merck Life Science, Milan, Italy). FR054 was synthesized either by our laboratories or by WuXi AppTec Co., Ltd. (Tianjin, China) [ 13 , 14 ]. The RAS inhibitor BI-2852 was requested and obtained from Boehringer Ingelheim (Ingelheim am Rhein, Germany) [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, different studies have demonstrated that the inhibition of the HBP and/or protein glycosylation induces cancer cell growth arrest and death [ 12 ]. In this regard, we recently synthesized and preclinically validated a new inhibitor called FR054, which targets phosphoglucomutase 3 (PGM3), the enzyme catalyzing the conversion of N -acetylglucosamine-6-phosphate (Glc N Ac-6P) in N -acetylglucosamine-1-phosphate (Glc N Ac-1P), and attenuates the HBP flux [ 13 , 14 ]. Importantly, FR054 is able to induce proliferation arrest and death in breast and pancreatic cancer cells and significantly reduces the growth of breast and pancreatic tumors in xenograft and PDX mice [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Ricciardiello

Bergamaschi

Vitto

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Ricciardiello

Bergamaschi

Vitto

et al. 2021

Cells

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“…For example, the recently developed FR054 showed inhibitory activity against PGM3 (Table ). , GAL-012 and the UTP a , b -methylenebisphosphonate analogue (meUTP) were synthesized as inhibitors to eukaryotic UAP1 (Table ). , Due to the critical role in the regulation of UDP-GlcNAc, HBP-targeting drugs may have attractive utility as therapeutics (which will be discussed in the following sections).…”

Section: Characterization Of Hbp and Udp-glcnacmentioning

confidence: 99%

“…PGM3, the third enzyme in the HBP, represents another target for cancer therapy. FR054 (Table ), a specific inhibitor to PGM3, has been designed and used in several preclinical studies recently. ,, One study revealed FR054 efficiently induces an early decrease of intracellular UDP-GlcNAc and hence diminishes O-GlcNAc and N-glycosylation, leading to reduced breast cancer cell adhesion and migration . Moreover, FR054 represses tumor growth in a xenograft mice mode.…”

Section: Biomedical Applicationsmentioning

confidence: 99%

Analytical and Biochemical Perspectives of Protein O-GlcNAcylation

2021

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Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is a unique monosaccharide modification discovered in the early 1980s. With the technological advances in the past several decades, great progress has been made to reveal the biochemistry of O-GlcNAcylation, the substrates of O-GlcNAcylation, and the functional importance of protein O-GlcNAcylation. As a nutrient sensor, protein O-GlcNAcylation plays important roles in almost all biochemical processes examined. Although the functional importance of O-GlcNAcylation of proteins has been extensively reviewed previously, the chemical and biochemical aspects have not been fully addressed. In this review, by critically evaluating key publications in the past 35 years, we aim to provide a comprehensive understanding of this important post-translational modification (PTM) from analytical and biochemical perspectives. Specifically, we will cover (1) multiple analytical advances in the characterization of O-GlcNAc cycling components (i.e., the substrate donor UDP-GlcNAc, the two key enzymes O-GlcNAc transferase and O-GlcNAcase, and O-GlcNAc substrate proteins), (2) the biochemical characterization of the enzymes with a variety of chemical tools, and (3) exploration of O-GlcNAc cycling and its modulating chemicals as potential biomarkers and therapeutic drugs for diseases. Last but not least, we will discuss the challenges and possible solutions for basic and translational research of protein O-GlcNAcylation in the future.

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Unleashing the Power of Domino Reactions on Carbohydrates: State of the Art

Antonini,

Petrosilli,

Giussani

et al. 2024

Eur J Org Chem

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The intricate nature of carbohydrate structures has prompted the scientific community to seek efficient protocols for their manipulation. Lengthy synthetic pathways, often necessary to achieve complex sugar structures, pose challenges not only in terms of time and cost but also regarding environmental sustainability. Consequently, domino transformations serve as valuable tools in streamlining drug discovery processes. Sequential procedures involving fewer steps and minimal isolation/purification steps are particularly appealing to organic chemists in the field of carbohydrate chemistry. This review highlights several examples of domino transformations applied to carbohydrates, aiming to summarize their chemical potential in delivering sugar‐based compounds with significant applications in the generation of new chemical scaffolds for drug discovery and chemical biology.

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Design, Synthesis, and Preliminary Biological Evaluation of GlcNAc‐6P Analogues for the Modulation of Phosphoacetylglucosamine Mutase 1 (AGM1/PGM3)

Cited by 10 publications

References 26 publications

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Analytical and Biochemical Perspectives of Protein O-GlcNAcylation

Unleashing the Power of Domino Reactions on Carbohydrates: State of the Art

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