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Enhancing Solubility in VHL-Based PROTACs: Optimized USP7 Degraders for Improved Developability.

Sophie Wittenburg1, Maximilian R Zuleeg2, Kirsten Peter2

  • 1Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, DE-53121 Bonn, Germany.

Journal of Medicinal Chemistry
|July 17, 2025
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Summary
This summary is machine-generated.

Researchers improved the solubility of VHL-based proteolysis-targeting chimeras (PROTACs) by modifying their structure. This work enhances the development of PROTACs for potential in vivo applications.

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Molecular Biology

Background:

  • VHL-based proteolysis-targeting chimeras (PROTACs) face development challenges due to poor physicochemical properties like low aqueous solubility.
  • High total polar surface area (TPSA) and hydrogen-bond donor (HBD) counts contribute to these limitations.

Purpose of the Study:

  • To enhance the physicochemical properties of VHL-recruiting USP7 degraders.
  • To develop PROTACs with improved solubility while maintaining target degradation efficacy.

Main Methods:

  • Systematic adjustment of lipophilicity, HBD count, and TPSA in VHL-recruiting PROTACs.
  • Structural modifications of the VHL ligand, including scaffold constraints and addition of solubilizing groups.
  • Evaluation of USP7 degradation capability and target selectivity.

Main Results:

  • Achieved significantly improved aqueous solubility in novel VHL-based PROTACs.
  • PROTAC 40, featuring a dibasic piperazine, demonstrated a 170-fold increase in solubility over its predecessor.
  • Maintained potent USP7 degradation and target selectivity after structural modifications.

Conclusions:

  • Rational scaffold design is effective for creating solubility-enhanced VHL-based PROTACs.
  • The developed PROTACs show broad potential for drug development and in vivo applications.
  • The methodology may be adaptable for developing PROTACs targeting other E3 ligases.