title: Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Eva
authors.identifier: 0000-0002-2749-6347
authors.initials: E
authors.lastname: Altmann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Erbel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Renatus
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Schlierf
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Druet
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Kieffer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Mickael
authors.initials: M
authors.lastname: Sorge
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.|Novartis Institutes for BioMedical Research, 4560 Horton Street, Emeryville, CA, 94608-2916, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Pfister
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hassiepen
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Ruedisser
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ostermeier
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.|Pharma Research and Early Development, Roche Innovation Center Basel, 4070, Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.affiliation: Novartis Institutes for BioMedical Research, 4560 Horton Street, Emeryville, CA, 94608-2916, USA.|Centers for Therapeutic Innovation, Pfizer Inc., San Francisco, CA, 94158, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Jefferson
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Quancard
mesh_terms: D001665:Binding Sites; D000075686:COP9 Signalosome Complex / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D000075687:NEDD8 Protein / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007211:Indoles; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D021122:Protein Subunits; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; C000628447:SKP2 protein, human; D000075686:COP9 Signalosome Complex; D015032:Zinc
keywords: CSN5; azaindoles; inhibitors; metalloproteases; ubiquitin ligases