Screening of a DNA-encoded library from the DELopen platform with 3 isoforms of OGT yielded several binders.

Selecting a few binders for inhibition yielded hits with micromolar inhibition.

Modeling revealed that two new chemotypes of inhibitors were identified.

Studies with derivatives of the hits provided a direction for further optimization.

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.

O-GlcNAc transferase

Inhibition

DNA-encoded library

© 2024 The Authors. Published by Elsevier Inc.