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Azaindoles as zinc-binding small molecule inhibitors of the JAMM protease CSN5

Altmann, Eva, Schlierf, Anita, Schaefer, Michael, Renatus, Martin, Ruedisser, Simon, Erbel, Paulus, Ostermeier, Daniela, Druet, Adelaide, Kieffer, Laurence, Sorge, Mickael, Hassiepen, Ulrich, Jones, Matthew, Pfister, Keith, Jefferson, Ann, Martoglio, Bruno and Quancard, Jean (2017) Azaindoles as zinc-binding small molecule inhibitors of the JAMM protease CSN5. Angewandte Chemie, 56 (5). pp. 1294-1297. ISSN 1433-7851


The COP9 signalosome (CSN) is an eight-subunit protein complex which is an important regulator of Cullin-Ring E3 ubiquitin ligases (CRLs). CSN5 is the Zinc metalloprotease subunit of CSN and is responsible for the cleavage of the ubiquitin-like protein NEDD8 from CRLs. Blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state leading to their inactivation by inducing auto-ubiquitination and subsequent degradation. Consequently CRL substrates (e.g. tumor suppressors p27 and p21) are stabilized resulting in inhibition of cell proliferation. Thus pharmacological inhibition of CSN5 has the potential to offer a new therapeutic strategy for an efficacious treatment of CSN5 dependent cancers. A high-throughput screen (HTS) with the entire CSN complex led to the identification of an azaindole hit as a micromolar CSN5 inhibitor. Optimization of this hit resulted in a series of potent CSN5 inhibitors which stabilized neddylated Cullin-1 and led to the degradation of Skp2 in HCT116 cells. Furthermore these inhibitors demonstrated the expected functional effect on inhibiting viability of cancer cells. In addition a X-ray cocrystal structure elucidated the binding mode and revealed the N7 of the azaindole as a monodate ligand of the active site Zn2+ ion. The 7-azaindole motif represents a novel Zinc-binding scaffold for metalloproteases.

Item Type: Article
Keywords: CSN5 inhibitor • Azaindoles • COPS9 signalosome • Cullin E3 ubiquitin ligase • Cancer
Date Deposited: 22 Jan 2017 00:45
Last Modified: 22 Jan 2017 00:45


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