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Targeting the deubiquitinase USP7 for degradation with PROTACs.

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.

SUBMITTER: Murgai A

PROVIDER: S-EPMC9710854 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Targeting the deubiquitinase USP7 for degradation with PROTACs.

Murgai Arunima A Sosič Izidor I Gobec Martina M Lemnitzer Patricia P Proj Matic M Wittenburg Sophie S Voget Rabea R Gütschow Michael M Krönke Jan J Steinebach Christian C

Chemical communications (Cambridge, England) 20220804 63

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 ...[more]

PMID: 35852517

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