TY - JOUR
T1 - NF-κB inducing kinase (NIK) inhibitors
T2 - Identification of new scaffolds using virtual screening
AU - Mortier, J.
AU - Masereel, B.
AU - Frederick, R.
AU - Remouchamps, C.
AU - Ganeff, C.
AU - Piette, J.
N1 - Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/8/1
Y1 - 2010/8/1
N2 - 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-κB inducing kinase (NIK), a key enzyme of the NF-κB 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 LTβR, 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 value of 51 and 90 μM, respectively. This study opens new perspectives in the field of the NF-κB alternative pathway inhibition.
AB - 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-κB inducing kinase (NIK), a key enzyme of the NF-κB 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 LTβR, 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 value of 51 and 90 μM, respectively. This study opens new perspectives in the field of the NF-κB alternative pathway inhibition.
UR - http://www.scopus.com/inward/record.url?scp=77955426473&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2010.06.027
DO - 10.1016/j.bmcl.2010.06.027
M3 - Article
AN - SCOPUS:77955426473
SN - 0960-894X
VL - 20
SP - 4515
EP - 4520
JO - Bioorganic and medicinal chemistry letters
JF - Bioorganic and medicinal chemistry letters
IS - 15
ER -