Small Molecule Inhibitors of Mucin-Type O-Linked Glycosylation from a Uridine-Based Library

Hang, Howard C.; Yu, Chong; Hagen, Karl S.; Tian, E; Winans, Katharine A.; Tabak, Lawrence A.; Bertozzi, Carolyn R.

doi:10.1016/j.chembiol.2004.02.023

Cited by 64 publications

(62 citation statements)

References 59 publications

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“…They also inhibit other members of the family (with IC50 values in the range 5-40 µM); however, pp-GalNAc-T6 was not tested. No inhibition of other sugar transferases was detected [66]. These data suggest that these inhibitors are specific to the pp-GalNAc-T family, but do not differentiate between family members.…”

Section: Potential As a Drug Targetmentioning

confidence: 67%

“…Both compounds incorporate a trihydroxylated benzene group (Scheme 2). The IC50 values for inhibition of pp-GalNAc-T1 were in the 20-25 µM range for both compounds [66]. They also inhibit other members of the family (with IC50 values in the range 5-40 µM); however, pp-GalNAc-T6 was not tested.…”

Section: Potential As a Drug Targetmentioning

confidence: 99%

“…The names are those used in the original paper reporting their synthesis and inhibitory potential [66].…”

Section: Figure and Scheme Legendsmentioning

confidence: 99%

“…These methods would be difficult to carry out with a large number of compounds (typically >500,000 in a high throughput screen) [1]. An enzyme-linked lectin assay (ELLA) has been developed in which glycosylation of an immobilised peptide substrate is detected with a lectin linked to horse radish peroxidase [66]. This has some potential for development into a highly parallel, high throughput assay format.…”

Section: Potential As a Drug Targetmentioning

confidence: 99%

“…Screening of a library of over 1300 uridine derivatives using an enzyme-linked lectin assay (ELLA) identified two compounds which inhibit pp-GalNAc-T1 [66]. Both compounds incorporate a trihydroxylated benzene group (Scheme 2).…”

Section: Potential As a Drug Targetmentioning

confidence: 99%

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UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

Banford¹,

Timson

2016

CCDT

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UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-6 (pp-GalNAc-T6) is a member of the N-acetyl-D-galactosamine transferase family. It catalyzes the addition of N-acetyl-D-galactosamine to proteins, often the first step in Oglycosylation of proteins. Glycosylated proteins play important roles in vivo in the cell membrane. These are often involved in cell-cell adhesion, cytoskeleton regulation and immune recognition. pp-GalNAc-T6 has been shown to be upregulated in a number of types of cancer. Abnormally glycosylated forms of mucin 1 (substrate of the enzyme), are used clinically as a biomarker for breast cancer. There is potential for other products of the pp-GalNAc-T6 catalyzed reaction to be used. It is also possible that pp-GalNAc-T6 itself could be used as a biomarker, since levels of this protein tend to be low in nonmalignant tissues. pp-GalNAc-T6 has been implicated in malignant transformation and metastasis of cancer cells. As such, it has considerable potential as a target for chemotherapy. To date, no selective inhibitors of the enzyme have been identified. However, general inhibitors of the enzyme family result in reduced cell surface Olinked glycosylation and induce apoptosis in cultured cells. Thus, a selective inhibitor of pp-GalNAc-T6 is likely to target cancer cells and could be developed into a novel anticancer therapy.

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Section: Potential As a Drug Targetmentioning

confidence: 67%

Section: Potential As a Drug Targetmentioning

confidence: 99%

“…The names are those used in the original paper reporting their synthesis and inhibitory potential [66].…”

Section: Figure and Scheme Legendsmentioning

confidence: 99%

Section: Potential As a Drug Targetmentioning

confidence: 99%

Section: Potential As a Drug Targetmentioning

confidence: 99%

See 3 more Smart Citations

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

Banford¹,

Timson

2016

CCDT

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Glycosylation of Proteins in the Golgi Apparatus

Desko

Kohler

2008

Wiley Encyclopedia of Chemical Biology

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Oligosaccharides are essential for interactions of cells with their environments. These complex carbohydrates are often found covalently attached to proteins embedded in eukaryotic cell membranes. Protein glycosylation is heterogeneous; this heterogeneity stems from the biosynthesis of these polymers. As proteins destined for secretion or cell‐surface presentation traffic through the endoplasmic reticulum and the Golgi apparatus, they are modified with sugars in a stepwise fashion by enzymes called glycosyltransferases. The differential expression of these enzymes leads to a multiplicity of specific oligosaccharides both among and within cells because not all cells contain all enzymes and because not all substrate proteins will encounter every enzyme. Although myriad oligosaccharides are found attached to proteins, most of these diverse structures can be grouped into several classes of glycans. In this article, we will discuss some of the most common forms of Golgi protein glycosylation: mucin‐type O ‐linked glycosylation, N ‐linked glycosylation, and the formation of glycosaminoglycans. In addition, we will briefly consider some less common, but essential, forms of glycosylation.

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High‐Throughput Screening for Inhibitors of Sialyl‐ and Fucosyltransferases

Rillahan

Brown

et al. 2011

Angewandte Chemie

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Sweet Screens: The promiscuity of sialyl-and fucosyltransferases has been exploited to develop a high-throughput screening (HTS) platform wherein transfer of a fluorescent analog of the natural donor substrate to a glycoprotein acceptor results in a robust fluorescence polarization readout. The use of this method to screen 16,000 compounds against 5 different glycosyltransferases has identified a panel of interesting inhibitors. KeywordsCarbohydrates; Fucose; Glycoproteins; Glycosyltransferase; Sialic Acid Sialyl-and fucosyltransferases decorate glycans of glycoproteins and glycolipids with terminal sialic acid and fucose residues, creating diverse structures recognized as ligands by pathogens and mammalian glycan binding proteins. [1] Their synthesis is carried out by the regulated expression of 20 sialyltransferase (ST) and 14 fucosyltransferase (FUT) genes that are highly conserved in mammalian species, each of which exhibits high specificity for their donor and acceptor substrates, giving rise to terminal sequences expressed in a cell type specific manner. Although phenotypes of knock-out mice have validated several of these enzymes as drug targets for the treatment of autoimmune disorders (ST6Gal I and ST3Gal I) and chronic inflammation (FUT7), [1b] no small molecule inhibitors have yet emerged.A limitation in identifying glycosyltransferase (GT) inhibitors has been the lack of simple and robust assays for high throughput screening (HTS) of compound libraries. Although a number of approaches have been used to screen for GT inhibitors, they comprise nonhomogeneous multi-step formats, or are designed for screening a few specific enzymes. [2] Here we report a fluorescence polarization (FP) based assay system that is broadly applicable to members of the ST and FUT families. Since STs and FUTs are well

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Small Molecule Inhibitors of Mucin-Type O-Linked Glycosylation from a Uridine-Based Library

Cited by 64 publications

References 59 publications

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase- 6 (pp-GalNAc-T6): Role in Cancer and Prospects as a Drug Target

Glycosylation of Proteins in the Golgi Apparatus

High‐Throughput Screening for Inhibitors of Sialyl‐ and Fucosyltransferases

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