2. Academic Validation
  3. Enhancing Solubility in VHL-Based PROTACs: Optimized USP7 Degraders for Improved Developability

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

  • J Med Chem. 2025 Jul 17. doi: 10.1021/acs.jmedchem.5c00718.
Sophie Wittenburg 1,  Maximilian R Zuleeg 2,  Kirsten Peter 2,  Patricia Lemnitzer 2,  Rabea Voget 1,  Aleša Bricelj 3,  Martina Gobec 3,  Nele Dierlamm 4,  Michael B Braun 4,  Thomas M Geiger 5,  Christopher Heim 4 6,  Alicia Stakemeier 7,  Karl G Wagner 7,  Radosław P Nowak 5,  Marcus D Hartmann 4,  Izidor Sosič 3,  Michael Gütschow 1,  Jan Krönke 2 8 9,  Christian Steinebach 1
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, DE-53121 Bonn, Germany.
  • 2 Department of Internal Medicine with Focus on Hematology, Oncology and Tumor Immunology, Charite, Hindenburgdamm 30, DE-12203 Berlin, Germany.
  • 3 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
  • 4 Max Planck Institute for Biology, DE-72076 Tübingen, Germany.
  • 5 Institute of Structural Biology, Medical Faculty, University of Bonn, DE-53127 Bonn, Germany.
  • 6 NanoTemper Technologies GmbH, DE-81379 Munich, Germany.
  • 7 Pharmaceutical Institute, Department of Pharmaceutical Technology and Biopharmaceutics, University of Bonn, DE-53121 Bonn, Germany.
  • 8 Universitätsmedizin Greifswald, DE-17489 Greifswald, Germany.
  • 9 German Cancer Consortium (DKTK), Partner Site Berlin, DKFZ and Charité-Universitätsmedizin Berlin, DE-12203 Berlin, Germany.
PMID: 40673806 DOI: 10.1021/acs.jmedchem.5c00718
Abstract

Limited aqueous solubility, high total polar surface area (TPSA), and high hydrogen-bond donor (HBD) counts have hampered the clinical development of VHL-based proteolysis-targeting chimeras (PROTACs). This study explores strategies to enhance the physicochemical properties of VHL-recruiting USP7 degraders. By adjusting lipophilicity, HBD count, and TPSA, we created degraders with improved solubility while maintaining their USP7 degradation capability. Structural modifications at the VHL ligand included a constrained six-membered ring in the peptidic scaffold and the addition of solubilizing groups. These changes enhanced aqueous solubility without compromising degradation performance. A key example is PROTAC 40, modified with a dibasic piperazine, which exhibits a 170-fold increase in solubility over its predecessor while retaining strong target selectivity. The findings demonstrate that rational scaffold design can yield solubility-enhanced VHL-based PROTACs with broad potential for drug development. This methodology may also be applicable to other E3 Ligases, supporting the development of degraders suitable for in vivo use.

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