Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels
Abstract
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.
Article and author information
Author details
Funding
National Institutes of Health (1R21DE026714)
- Adam Linstedt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christopher G Burd, Yale School of Medicine, United States
Ethics
Animal experimentation: Protocols, handling, and care of the mice conformed to protocols approved by the Institutional Animal Care and Use Committee of Carnegie Mellon University.(CMU IACUC protocol AS16-005).
Version history
- Received: December 8, 2016
- Accepted: March 30, 2017
- Accepted Manuscript published: March 31, 2017 (version 1)
- Version of Record published: April 27, 2017 (version 2)
- Version of Record updated: May 12, 2017 (version 3)
Copyright
© 2017, Song & Linstedt
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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