%0 Journal Article
%A Wittenburg, Sophie
%A Zuleeg, Maximilian R
%A Peter, Kirsten
%A Lemnitzer, Patricia
%A Voget, Rabea
%A Bricelj, Aleša
%A Gobec, Martina
%A Dierlamm, Nele
%A Braun, Michael B
%A Geiger, Thomas M
%A Heim, Christopher
%A Stakemeier, Alicia
%A Wagner, Karl G
%A Nowak, Radosław P
%A Hartmann, Marcus D
%A Sosič, Izidor
%A Gütschow, Michael
%A Krönke, Jan
%A Steinebach, Christian
%T Enhancing Solubility in VHL-Based PROTACs: Optimized USP7 Degraders for Improved Developability.
%J Journal of medicinal chemistry
%V 68
%N 15
%@ 0095-9065
%C Washington, DC
%I ACS
%M DKFZ-2025-01446
%P 15711-15737
%D 2025
%Z 2025 Aug 14;68(15):15711-15737
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40673806
%R 10.1021/acs.jmedchem.5c00718
%U https://inrepo02.dkfz.de/record/302999