Targeting the deubiquitinase USP7 for degradation with PROTACs
Arunima Murgai, Izidor Sosič, Martina Gobec, Patricia Lemnitzer, Matic Proj, Sophie Wittenburg, Rabea Voget, Michael Gütschow, Jan Krönke, Christian Steinebach
Abstract
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 a ubiquitin-specific protease 7 (USP7) inhibitor scaffold to degrade USP7. By investigating several linker and E3 ligand types, including novel cereblon recruiters, we discovered a highly selective USP7 degrader tool compound that induced apoptosis of USP7-dependent cancer cells. This work represents one of the first DUB degraders and unlocks a new drug target class for protein degradation.