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

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.