Scientific Synopsis
OGT is a central enzyme involved in the post-translational modifications of proteins; it catalyzes the transfer of N-acetylglucosamine (GlcNAc) from uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to the serine and threonine residues of nucleocytoplasmic proteins. This post-translational modification has been implicated in gene transcription, stress response and nutrient sensing. The activity of OGT is tightly linked to the metabolic status of cells. Dysregulated O-GlcNAcylation has been linked to cancer, diabetic complications and other pathologies. To better understand the various functions of OGT in transcriptional, signaling and metabolic pathways, the project team sought to design a small molecule inhibitor of OGT. Using the NCATS qualitative high-throughput platform and following iterative rounds of structure-activity relationship (SAR) studies, the team developed OSMI-1, a cell-permeable small molecule inhibitor of OGT. Further medicinal chemistry efforts are currently underway to improve the activity and pharmacologic profile of our OGT inhibitors.
The scheme on the left illustrates how OSMI-1 inhibits the ability of OGT to catalyze the transfer of GlcNAc from UDP-GlcNAc to the serine and threonine residues of proteins. The Western blot gels on the right show that incubation with OSMI-1 drastically reduces the N-acetylglucosylation of proteins in the cell. (Reprinted with permission from Ortiz-Meoz R, et al. A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015;10(6):1392–7. Copyright 2015 American Chemical Society.
Lead Collaborators
- Craig J. Thomas, Ph.D.,NCATS, NIH
- Damien Y. Duveau, Ph.D., NCATS, NIH
- Suzanne Walker, Ph.D., Harvard University
Publications
- Ortiz-Meoz RF, Jiang J, Lazarus MB, Orman M, Janetzko J, Fan C, Duveau DY, Tan ZW, Thomas CJ, Walker S. A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015 Jun 19;10(6):1392–7. doi: 10.1021/acschembio.5b00004
- Itkonen HM, Gorad SS, Duveau DY, Martin SE, Barkovskaya A, Bathen TF, Moestue SA, Mills IG. Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism. Oncotarget. 2016 Mar 15;7(11):12464–76. doi: 10.18632/oncotarget.7039
Public Health Impact
The OGT enzyme plays diverse roles in mammalian cell biology. To better understand the precise roles of OGT in cell function and disease states, targeted OGT inhibitors are needed. The goal is to develop and optimize such an inhibitor.