Article ; Online: Discovery of two non-UDP-mimic inhibitors of O-GlcNAc transferase by screening a DNA-encoded library.
2024 Volume 147, Page(s) 107321
Abstract: Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic ... ...
| Abstract | Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic the main interactions of glycosyl donor UDP-GlcNAc with the enzyme. Until recently, screening of DNA-encoded libraries for discovering hits against protein targets was dedicated to a few laboratories around the world, but has become accessible to wider public with the recent launch of the DELopen platform. Here we report the results and follow-up of a DNA-encoded library screening by using the DELopen platform. This led to the discovery of two new hits with structural features not resembling UDP. Small focused libraries bearing those two scaffolds were made, leading to low micromolar inhibition of OGT and elucidation of their structure-activity relationship. |
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| MeSH term(s) | N-Acetylglucosaminyltransferases/antagonists & inhibitors ; N-Acetylglucosaminyltransferases/metabolism ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/chemical synthesis ; Structure-Activity Relationship ; DNA/chemistry ; DNA/metabolism ; Humans ; Drug Discovery ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/chemical synthesis ; Molecular Structure ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Uridine Diphosphate/metabolism ; Uridine Diphosphate/chemistry |
| Chemical Substances | O-GlcNAc transferase |
| Language | English |
| Publishing date | 2024-03-29 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 120080-x |
| ISSN | 1090-2120 ; 0045-2068 |
| ISSN (online) | 1090-2120 |
| ISSN | 0045-2068 |
| DOI | 10.1016/j.bioorg.2024.107321 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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