Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

Wennekes, Tom; Meijer, Alfred J.; Groen, Albert K.; Boot, Rolf G.; Groener, J.E.M.; Eijk, Marco van; Ottenhoff, Roelof; Bijl, Nora; Ghauharali, Karen; Song, Hang; O'Shea, Tom J; Liu, Hanlan; Yew, Nelson S.; Copeland, Diane; Berg, Richard J van den; Marel, Gijsbert A. van der; Overkleeft, Herman S.; Aerts, Johannes M. F. G.

doi:10.1021/jm901281m

Cited by 89 publications

(84 citation statements)

References 41 publications

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“…Genz-123346 is a novel analogue of PDMP with improved specificity for inhibiting glucosylceramide synthase (19,28,29). In this study, we examined the chemosensitizing effect of Genz-123346 on tumor cells and provide evidence suggesting that modulation of P-gp function may be the primary mode of action.…”

Section: Introductionmentioning

confidence: 99%

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Madden¹

2011

Int J Oncol

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Abstract. Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at nontoxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug reisistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.

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Section: Introductionmentioning

confidence: 99%

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Madden¹

2011

Int J Oncol

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“…We identified the C-5-epimer of 3, L-ido-AMP-DNM 4 as a much-improved compound in this respect. 35 Its GCS inhibitory activity is equal to, or even slightly better than, AMP-DNM 3, whereas its activity toward GBA1 and GBA2 is about a 10-fold lower and its activity toward intestinal glycosidases next to nonexistent. Dividing GBA1 inhibition potency by that found for GCS gives insight in enzyme selectivity, and doing so for the three iminosugars mentioned reveals that replacing the butyl group in 1 for the bulky, hydrophobic adamantanemethyloxypentyl group as in 3 gives a selectivity drop (from 8 to 1).…”

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confidence: 96%

“…We found that AMP-DNM 3 can be used to improve glycemic control in obese rodents thanks to its dual action to both buffer carbohydrate assimilation (through inhibition of intestinal glycosidases) and reduce visceral glycolipid levels (inhibition of GCS). 35 At the same time, we recognized that to realize effective therapeutic applications based on modulating GCS as the single target, compounds need be developed that combine GCS inhibitory potency at least equal to that of AMP-DNM 3 with a much-reduced activity toward other glyco-processing enzyme. It should be noted here that 1-butyldeoxynojirimycin 1 is in fact a rather moderate GCS inhibitor with quite some activity against other enzymes.…”

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confidence: 99%

“…The preparation of the iminosugar library follows wellestablished routes of synthesis previously reported by us 35,39 and others. 40,41 Details on the preparation and characterization of all compounds are provided in the Supporting Information.…”

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confidence: 99%

“…The first three entries depict the results obtained by leads 1, 3, and 4 data, which corroborates our previous results. 35 In general, extension of the Nalkyl chain results in more potent GCS inhibitors. 46 Within the D-gluco series, the N-alkyl derivatives (1 and 5-9) are moderate GCS inhibitors, with octyl and nonyl deoxynojirimycin derivatives 8 and 9 being the most potent.…”

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Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Ghisaidoobe

Bikker

Bruijn

et al. 2010

ACS Med. Chem. Lett.

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Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated L-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

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Competitive and Covalent Inhibitors of Human Lysosomal Retaining Exoglucosidases

Breen

Artola

et al. 2018

Encyclopedia of Life Sciences

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Deficiency in human acid glucosylceramidase (GBA1, a retaining β‐glucosidase) causes the lysosomal sphingolipid storage disorder Gaucher disease, whereas deficiency in human acid α‐glucosidase (GAA, a retaining α‐glucosidase) triggers the lysosomal glycogen storage disorder Pompe disease. Both enzymes process their substrate following a two‐step double‐displacement mechanism involving a covalent enzyme–substrate intermediate. Structural analysis of glycosidases complexed to substrates and inhibitors has provided insight into the reaction coordinates followed by glycosidases during catalytic hydrolysis and has assisted in the design of potent and selective inhibitors. Competitive and covalent inhibitors of both GBA1 and GAA have been developed in the past decades, for fundamental studies, as diagnostics tools, leads for drug development and therapeutic drugs for the clinical treatment of lysosomal storage diseases. Key Concepts The structural and functional diversity of glycoconjugates is reflected by the vast number of glycoprocessing enzymes encountered in all domains of life. Retaining glycosidases form a covalent intermediate during substrate processing, whereas inverting glycosidases do not. Competitive and covalent retaining glycosidase inhibitors exist, whereas inverting glycosidases can normally only be blocked by competitive inhibitors. Both covalent and competitive glycosidase inhibitors are found in nature and serve as inspiration for the design of synthetic inhibitors. Structural analysis of glycosidases complexed to substrates and inhibitors provides insight into the reaction coordinates followed by glycosidases during the catalytic cycle. Conformational analysis of the reaction coordinate of glycosidases is key in the design of potent and selective inhibitors. Glycosidase inhibitors may serve as leads for drug development. Activity‐based glycosidase probes can be applied in the discovery of glycosidase activities. Activity‐based probes are useful starting points for the development of diagnostics assays in disease areas in which glycosidase activities are involved. Genetic deficiency in glycosidases is the basis of numerous inherited disorders including Gaucher disease and Pompe disease.

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Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

Cited by 89 publications

References 41 publications

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Competitive and Covalent Inhibitors of Human Lysosomal Retaining Exoglucosidases

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