NF-κB inducing kinase (NIK) inhibitors: Identification of new scaffolds using virtual screening

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-kappa B inducing kinase (NIK), a key enzyme of the NF-kappa B 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 LT beta R, 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 IC50 value of 51 and 90 mu M, respectively. This study opens new perspectives in the field of the NF-kappa B alternative pathway inhibition. (C) 2010 Elsevier Ltd. All rights reserved.