title: NF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening.
abstract: As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition.
authors.affiliation: Drug Design and Discovery Center, University of Namur, FUNDP, Namur, Belgium.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mortier
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Caroline
authors.initials: C
authors.lastname: Remouchamps
authors.forename: Corinne
authors.initials: C
authors.lastname: Ganeff
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frederick
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000097782:NF-kappaB-Inducing Kinase