From the abstract: In this study, we present a comprehensive peptidomimetic structure–activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.
Thank You for sharing Joel Walker
Product Manager | Bio-Techne | PhD Chemical Biology | Targeted Protein Degradation & Induced Proximity
2moThanks for sharing Joel Walker, always exciting to see advancements in VHL ligands especially the development of GNE7599, with its picomolar binding affinity and improved bioavailability. This is a game-changer for VHL based degrader development, however other scientists have also developed innovative ways to achieve degradation of a target protein without optimized VHL ligands, as you can see at the 5th Virtual Bio-Techne Targeted Protein Degradation and Induced Proximity Symposium on July 10th. Registration Link - https://bit.ly/4c3wNNp"