title: Discovery of Cell-Permeable O-GlcNAc Transferase Inhibitors via Tethering in Situ Click Chemistry.
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.
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences , Beijing 100049, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University , Beijing 100191, China.
authors.forename: Yue
authors.identifier: 0000-0002-2574-6306
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University , Beijing 100191, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, China.
authors.forename: Lianwen
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019556:COS Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002522:Chlorocebus aethiops; D002853:Chromatography, Liquid; D057930:Click Chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase