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Azaindoles as Zinc‐Binding Small‐Molecule Inhibitors of the JAMM Protease CSN5
Author(s) -
Altmann Eva,
Erbel Paul,
Renatus Martin,
Schaefer Michael,
Schlierf Anita,
Druet Adelaide,
Kieffer Laurence,
Sorge Mickael,
Pfister Keith,
Hassiepen Ulrich,
Jones Matthew,
Ruedisser Simon,
Ostermeier Daniela,
Martoglio Bruno,
Jefferson Anne B.,
Quancard Jean
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201608672
Subject(s) - nedd8 , cop9 signalosome , protein subunit , chemistry , ubiquitin , biochemistry , cleavage (geology) , protease , protein degradation , microbiology and biotechnology , biology , enzyme , ubiquitin ligase , paleontology , peptide hydrolases , fracture (geology) , gene
CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin‐RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto‐ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active‐site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells.