An Efficient Approach to the Discovery of Potent Inhibitors against Glycosyltransferases

Hosoguchi, Kensaku; Maeda, Takahiro; Furukawa, Yoshihiro; Shinohara, Yasuro; Hinou, Hiroshi; Sekiguchi, Mitsuaki; Togame, Hiroko; Takemoto, Hiroshi; Kondo, Hirosato; Nishimura, Shin‐Ichiro

doi:10.1021/jm100612r

Cited by 45 publications

(35 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…But the modification of Neu5Ac of CMP-Neu5Ac for seeking effective sialyltransferase inhibitors is worth exploring . Hosoguchi and co-workers reported that modification at C-5 position of CMP-Neu5Ac with bulky steroid analog (7) had strong impact to the catalytic action by sialyltransferases [26]. It showed that compound 7 is a highly promising inhibitor against α2,3-ST (ST3Gal III) (IC 50 = 8.2 μM).…”

Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

Sialic acids, existing as terminal sugars of glycoconjugates, play important roles in various physiological and pathological processes, such as cell-cell adhesion, immune defense, tumor cell metastasis, and inflammation. Sialyltransferases (STs) catalyze the transfer of sialic acid residues to non-reducing oligosaccharide chains of proteins and lipids, using cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) as the donor. Elevated sialyltransferase activity leads to overexpression of cell surface sialic acids and contributes to many disease developments, such as cancer and inflammation. Therefore, sialyltransferases are considered as potential drug targets for disease treatment. Inhibitors of sialyltransferases thus are of medicinal interest, especially for the cancer therapy. In addition, sialyltransferase inhibitors are useful tool to study sialyltransferase function and related mechanisms. This review highlights recent development of inhibitors of sialyltransferases reported since 2004. The inhibitors are summarized as eight groups: 1) sialic acid analogs, 2) CMP-sialic acid analogs, 3) cytidine analogs, 4) oligosaccharide derivatives, 5) aromatic compounds, 6) flavonoids, 7) lithocholic acid analogs, and 8) others. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.

show abstract

Section: Cmp-sialic Acid Analogsmentioning

confidence: 99%

Sialyltransferase inhibition and recent advances

Wang

Liu

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

show abstract

“…In 2011, the first two crystal structures of human OGT were solved: a binary complex with uridine 5'-diphosphate (UDP) and a ternary complex with UDP and a peptide substrate, including the catalytic region (PDB codes: 3PE3 and 3PE4) [536]. Additional reports discussing the mechanism underlining OGT and OGA activities as well as smallmolecule inhibitors and drug discovery methodologies have recently appeared [537][538][539][540][541][542][543]. Glycosyltransferases have been recently used to derive glycosylated analogues of novobiocin with improved activity against several cancer cell lines [544].…”

Section: Glycosylationmentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

View full text Add to dashboard Cite

Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

show abstract

“…Plant-derived or synthetic inhibitors of the sialic acid machinery are rare and show low efficacy (9). The rational design of sialic acid analogues that interfere with the cellular sialic acid synthesis machinery might form a more promising approach (10)(11)(12). Here sialyltransferases constitute an attractive target as they have been shown to underlie aberrant cancer sialylation.…”

Section: Introductionmentioning

confidence: 99%

Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth

Büll

Boltje

Wassink

et al. 2013

Molecular Cancer Therapeutics

157

133

View full text Add to dashboard Cite

Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F ax -Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F ax -Neu5Ac readily caused depletion of a2,3-/a2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F ax -Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F ax -Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F ax -Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy. Mol Cancer Ther; 12(10); 1935-46. Ó2013 AACR.

show abstract

An Efficient Approach to the Discovery of Potent Inhibitors against Glycosyltransferases

Cited by 45 publications

References 65 publications

Sialyltransferase inhibition and recent advances

Sialyltransferase inhibition and recent advances

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth

Contact Info

Product

Resources

About