Potency-enhanced peptidomimetic VHL ligands with improved oral bioavailability
Hao Wu
Scientist 3, Genentech, Inc.
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. VHL functions as a substrate receptor of the Cullin RING E3 ligase CRL2. Given its potential as a therapeutic target for modulating the hypoxic stress response, such as in anemia, and its utility in generating bivalent degraders, we aimed to enhance the existing VHL ligands. In this study, we present a comprehensive peptidomimetic structure-activity relationship (SAR) approach, combined with cellular nanoBRET target engagement assays. Through systematic modifications on the left-hand side of the molecule, we identified the 1,2,3-triazole group as an optimal substitute for the amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the right-hand side 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 will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.
Dr. Hao Wu is currently Scientist 3 at Genentech, Departments of Early Discovery Biochemistry, Peptide Therapeutics Division. He joined the peptide medicinal chemistry lab led by Dr. Jakob Fuhrmann in Genentech 6 years ago. Since then, he has been involved in many projects to improve the drug-like properties of peptides, using rational design, structure-guided design, and combinatorial chemistry approach. Before joining Genentech, Dr. Wu had postdoctoral training in Prof. Thomas Kodadek’s lab at The Scripps Research Institute – Florida and obtained his Ph.D. in Prof. Shaoqin Yao’s lab, Department of Chemistry, National University of Singapore.