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Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability.

Hao Wu1, Jeremy Murray2, Noriko Ishisoko3

  • 1Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.

Journal of Medicinal Chemistry
|May 29, 2024
PubMed
Summary

Researchers optimized VHL ligands using structure-activity relationship studies and NanoBRET assays. The new GNE7599 ligand shows 10-fold higher binding activity and improved oral bioavailability for targeted protein degradation research.

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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.