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.