Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels
Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNA...
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doaj-ffb0661ea53b424e96b02bf8103656c72021-05-05T13:23:10ZengeLife Sciences Publications LtdeLife2050-084X2017-03-01610.7554/eLife.24051Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levelsLina Song0Adam D Linstedt1https://orcid.org/0000-0003-0754-1638Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United StatesDepartment of Biological Sciences, Carnegie Mellon University, Pittsburgh, United StatesSmall molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.https://elifesciences.org/articles/24051O-glycosylationbiosensordrug-like inhibitormetastasisFGF23 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lina Song Adam D Linstedt |
spellingShingle |
Lina Song Adam D Linstedt Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels eLife O-glycosylation biosensor drug-like inhibitor metastasis FGF23 |
author_facet |
Lina Song Adam D Linstedt |
author_sort |
Lina Song |
title |
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels |
title_short |
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels |
title_full |
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels |
title_fullStr |
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels |
title_full_unstemmed |
Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels |
title_sort |
inhibitor of ppgalnac-t3-mediated o-glycosylation blocks cancer cell invasiveness and lowers fgf23 levels |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2017-03-01 |
description |
Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics. |
topic |
O-glycosylation biosensor drug-like inhibitor metastasis FGF23 |
url |
https://elifesciences.org/articles/24051 |
work_keys_str_mv |
AT linasong inhibitorofppgalnact3mediatedoglycosylationblockscancercellinvasivenessandlowersfgf23levels AT adamdlinstedt inhibitorofppgalnact3mediatedoglycosylationblockscancercellinvasivenessandlowersfgf23levels |
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