New scaffolds for O-GlcNAc transferase inhibition, by hit and synthetic route optimisation
Eekelen, Kevin van
MetadataShow full item record
Perturbations in O-GlcNAcylation, modulated by O-GlcNAc transferase (OGT) and O-GlcNAcase, have been observed in diabetes, cancer, cardiovascular disease, and Alzheimer’s disease. Therefore, OGT is an interesting therapeutic target for the medical community. Current potent OGT inhibitors usually lack target specificity, e.g., BZX2 and OSMI-1, or cell-permeability e.g. OSMI-4. To explore novel OGT inhibitors, hit optimisation was performed on the recently identified compound Vs-51, creating a small library. In total, five promising derivatives of Vs-51 were synthesised, of which the most potent one inhibited the enzyme with an IC50 of 27 ± 13 µM. Furthermore, the derivatives provided improved insight into potential Vs-51 enhancements. For the second part of this study, a DNA encoded library was used to find new scaffolds for OGT, leading to two promising hits. A new synthetic pathway was established for one of these hits (10115) while allowing easy derivatisation options. The ease of tunability of the provided scaffold through the here described synthesis route offers a potential new series of potent OGT inhibitors.