Discovery of two non-UDP-mimic inhibitors of O-GlcNAc transferase by screening a DNA-encoded library.

Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE

Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.

N-Acetylglucosaminyltransferases*/antagonists & inhibitors ; N-Acetylglucosaminyltransferases*/metabolism ; Enzyme Inhibitors*/pharmacology ; Enzyme Inhibitors*/chemistry ; Enzyme Inhibitors*/chemical synthesis ; DNA*/chemistry ; DNA*/metabolism ; Drug Discovery* ; Small Molecule Libraries*/chemistry ; Small Molecule Libraries*/pharmacology ; Small Molecule Libraries*/chemical synthesis; Structure-Activity Relationship ; Humans ; Molecular Structure ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Uridine Diphosphate/metabolism ; Uridine Diphosphate/chemistry

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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Keywords: DNA-encoded library; Inhibition; O-GlcNAc transferase

0 (O-GlcNAc transferase)

Date Created: 20240411 Date Completed: 20240516 Latest Revision: 20240520

20240520

10.1016/j.bioorg.2024.107321

38604018