A small molecule that inhibits OGT activity in cells.
O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of O-GlcNAc modification is still not well understood, and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here, we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein O-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface N- or O-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models.
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Rodrigo F
RF
Ortiz-Meoz
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Jiaoyang
J
Jiang
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Michael B
MB
Lazarus
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Marina
M
Orman
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
John
J
Janetzko
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Chenguang
C
Fan
‡National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States.
Damien Y
DY
Duveau
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Zhi-Wei
ZW
Tan
‡National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States.
Craig J
CJ
Thomas
†Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States.
Suzanne
S
Walker
D000818:Animals; D016466:CHO Cells; D002463:Cell Membrane Permeability; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D037102:Lectins / Q000737:chemistry / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000737:chemistry / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D037102:Lectins; D054852:Small Molecule Libraries; D014537:Uridine Diphosphate N-Acetylglucosamine; D014530:Uridine Diphosphate; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase