19482-24-7Relevant academic research and scientific papers
Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5
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
supporting information, p. 1294 - 1297 (2017/01/24)
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.
PHARMACEUTICAL COMPOUNDS
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Page/Page column 88-89, (2008/06/13)
The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH=CH, N=CH, CH=N, HN-C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
