Expanding the PROTAC Toolbox: Targeted Degradation of the Deubiquitinase USP7 in Cancer

Targeting deubiquitinating enzymes (DUBs) has emerged as a promising therapeutic approach in several human cancers and other diseases. DUB inhibitors are exciting pharmacological tools but often exhibit limited cellular potency. Here we report PROTACs based on an ubiquitin-specific protease 7 (USP7) inhibitor scaffold to degrade USP7. The hit compound CST967 caused highly selective degradation of USP7 and inhibited proliferation of USP7-dependent cancer cells. We present the first DUB degrader, which will be a useful tool to deepen our understanding of USP7.