Targeting the deubiquitinase USP7 for degradation with PROTACs.

Autor: Murgai A; Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. jan.kroenke@charite.de.; German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany., Sosič I; Faculty of Pharmacy, University of Ljubljana, SI-1000, Ljubljana, Slovenia., Gobec M; Faculty of Pharmacy, University of Ljubljana, SI-1000, Ljubljana, Slovenia., Lemnitzer P; Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. jan.kroenke@charite.de., Proj M; Faculty of Pharmacy, University of Ljubljana, SI-1000, Ljubljana, Slovenia., Wittenburg S; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany. c.steinebach@uni-bonn.de., Voget R; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany. c.steinebach@uni-bonn.de., Gütschow M; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany. c.steinebach@uni-bonn.de., Krönke J; Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. jan.kroenke@charite.de.; German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany., Steinebach C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany. c.steinebach@uni-bonn.de.
Jazyk: angličtina
Zdroj: Chemical communications (Cambridge, England) [Chem Commun (Camb)] 2022 Aug 04; Vol. 58 (63), pp. 8858-8861. Date of Electronic Publication: 2022 Aug 04.
DOI: 10.1039/d2cc02094g
Abstrakt: 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.
Databáze: MEDLINE
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