Breaking Barriers in PROTAC Design: Improving Solubility of USP7-Targeting Degraders

The development of von Hippel–Lindau (VHL) hijacking proteolysis-targeting chimeras (PROTACs) has been hindered by suboptimal physicochemical properties, including high total polar surface area (TPSA), high hydrogen bond donor (HBD) counts, and poor solubility. This study explores a novel approach to enhance the physicochemical characteristics of VHL-recruiting USP7 degraders while maintaining their efficacy. By systematically optimizing the lipophilicity, hydrogen bond donor count, and the TPSA of USP-targeting moieties, we designed a series of VHL-based degraders with improved solubility and target degradation potential. The introduction of a constrained six-membered ring in the VHL-binding scaffold or the incorporation of solubilizing groups in the VHL ligand moiety notably improved aqueous solubility without compromising degradation activity. Among the compounds resulting from the latter approach, the bis-basic piperazine-modified PROTAC 40 showed a remarkable 170-fold increase in solubility compared to its precursor while retaining high target selectivity and degradation efficiency. This study demonstrates that tailored modifications to the VHL-binding scaffold can yield solubility-enhanced PROTACs with broad applicability. The methodology may be extended to other E3 ligases to expand the arsenal of degraders for in vivo studies.