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
  • 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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