Design of OSMI-4 Analogs Using Scaffold Hopping: Investigating the Importance of the Uridine Mimic in the Binding of OGT Inhibitors

by Selleckchem | Sep 29 2023

β-N-Acetylglucosamine transferase (OGT) inhibition is considered an important topic in medicinal chemistry. The involvement of O-GlcNAcylation in several important biological pathways is pointing to OGT as a potential therapeutic target. The field of OGT inhibitors drastically changed after the discovery of the 7-quinolone-4-carboxamide scaffold and its optimization to the first nanomolar OGT inhibitor: OSMI-4. While OSMI-4 is still the most potent inhibitor reported to date, its physicochemical properties are limiting its use as a potential drug candidate as well as a biological tool. In this study, we have introduced a simple modification (elongation) of the peptide part of OSMI-4 that limits the unwanted cyclisation during OSMI-4 synthesis while retaining OGT inhibitory potency. Secondly, we have kept this modified peptide unchanged while incorporating new sulfonamide UDP mimics to try to improve binding of newly designed OGT inhibitors in the UDP-binding site. With the use of computational methods, a small library of OSMI-4 derivatives was designed, prepared and evaluated that provided information about the OGT binding pocket and its specificity toward quinolone-4-carboxamides.

Comments:

The study you mentioned focuses on the inhibition of β-N-Acetylglucosamine transferase (OGT), which is considered an important target in medicinal chemistry. OGT plays a role in O-GlcNAcylation, a post-translational modification involved in various biological pathways. Inhibiting OGT has the potential to impact these pathways and make OGT a therapeutic target.

The field of OGT inhibitors experienced a significant change with the discovery of the 7-quinolone-4-carboxamide scaffold, which served as a starting point for developing potent OGT inhibitors. Among these inhibitors, OSMI-4 stands out as the most potent reported to date. However, OSMI-4 has certain physicochemical properties that limit its utility both as a potential drug candidate and as a biological tool.

To address these limitations, the researchers in this study made a simple modification to the peptide part of OSMI-4. This modification, known as elongation, aimed to prevent unwanted cyclization during the synthesis of OSMI-4 while maintaining its inhibitory potency against OGT. Additionally, the modified peptide was kept unchanged, and new sulfonamide UDP mimics were incorporated to improve the binding of the newly designed OGT inhibitors in the UDP-binding site.

The researchers employed computational methods to design a small library of OSMI-4 derivatives based on their modifications. These derivatives were then synthesized, and their OGT inhibitory activity was evaluated. The study provided valuable information about the OGT binding pocket and its specificity toward quinolone-4-carboxamides, aiding in the design and development of novel OGT inhibitors.

Overall, the study aimed to overcome the limitations of OSMI-4 as a potential drug candidate by modifying its peptide part and incorporating new sulfonamide UDP mimics. The use of computational methods and the evaluation of the synthesized derivatives provided insights into the binding pocket of OGT and its preferences for quinolone-4-carboxamides, contributing to the advancement of OGT inhibitor research.