Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5
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- 作者：Dr. Eva Altmann ; Dr. Paul Erbel ; Dr. Martin Renatus ; Dr. Michael Schaefer ; Dr. Anita Schlierf ; Adelaide Druet ; Laurence Kieffer ; Mickael Sorge ; Keith Pfister ; Dr. Ulrich Hassiepen ; Matthew Jones ; Dr. Simon Ruedisser ; Daniela Ostermeier ; Dr. Bruno Martoglio ; Dr. Anne B. Jefferson and Dr. Jean Quancard
- 刊名：Angewandte Chemie International Edition
- 出版年：2017
- 出版时间：January 24, 2017
- 年：2017
- 卷：56
- 期：5
- 页码：1294-1297
- 全文大小：2195K
- ISSN：1521-3773
文摘
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.