Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability.
J Med Chem
; 67(11): 8585-8608, 2024 Jun 13.
Article
in En
| MEDLINE
| ID: mdl-38809766
ABSTRACT
The von Hippel-Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biological Availability
/
Von Hippel-Lindau Tumor Suppressor Protein
/
Peptidomimetics
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
United States