Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• The von Hippel-Lindau (VHL) protein is crucial for regulating cellular response to hypoxia.
• VHL ligands are key components in targeted protein degradation (TPD) strategies, including bivalent degraders.
• Enhancing VHL ligand potency and pharmacokinetic properties is vital for advancing TPD therapeutics.

Purpose of the Study:

• To optimize existing von Hippel-Lindau (VHL) ligands through a comprehensive peptidomimetic structure-activity relationship (SAR) approach.
• To identify novel VHL ligands with enhanced binding affinity and improved drug-like properties.
• To develop a valuable tool compound for VHL pathway research and TPD applications.

Main Methods:

• Systematic structure-activity relationship (SAR) analysis of peptidomimetic VHL ligands.
• Utilizing cellular NanoBRET target engagement assays to measure binding affinity.
• Incorporating chemical modifications, including 1,2,3-triazole substitution and conformational constraints.

Main Results:

• Identification of the 1,2,3-triazole group as a superior replacement for the left-hand side amide bond, increasing binding activity 10-fold.
• Development of highly potent VHL ligands with picomolar binding affinity.
• Achieved significantly improved oral bioavailability through conformational modifications.

Conclusions:

• The optimized VHL ligand, GNE7599, represents a significant advancement in VHL ligand development.
• GNE7599 demonstrates high potency and favorable pharmacokinetic properties, making it suitable for TPD research.
• This work provides a valuable tool compound for further investigation of the VHL pathway and the broader field of targeted protein degradation.