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Discovery of Cell-Permeable O-GlcNAc Transferase Inhibitors via Tethering in Situ Click Chemistry.

Authors :
Yue Wang
Jingjing Zhu
Lianwen Zhang
Source :
Journal of Medicinal Chemistry. Jan2017, Vol. 60 Issue 1, p263-272. 10p.
Publication Year :
2017

Abstract

O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic O-GlcNAcylation of nuclear and cytoplasmic proteins similar to phosphorylation. Discovery of cell-permeable OGT inhibitors is significant to clarify the function and regulatory mechanism of O-GlcNAcylation. This will establish the foundation for the development of therapeutic drugs for relevant diseases. Here, we report two cell-permeable OGT inhibitors (APNT and APBT), developed from low-activity precursors (IC50 > 1 mM) via "tethering in situ click chemistry (TISCC)". Both of them were able to inhibit O-GlcNAcylation in cells without significant effects on cell viability. Unusual noncompetitive inhibition of OGT was helpful to discover novel inhibitors and explore the regulatory mechanism of OGT. The development of these molecules validates that TISCC can be utilized to discover novel lead compounds from components that exhibited very weak binding to the target. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222623
Volume :
60
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
120717407
Full Text :
https://doi.org/10.1021/acs.jmedchem.6b01237