AbstractAs 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. Firstly, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kB activation pathway. Secondly, 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, 4Hisoquinoline-1,3-dione and 2,7-naphtydrine-1,3,6,8-tetrone which inhibit NIK with an IC50 value of 51 and 90 µM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathways inhibition.
|Date of Award||7 Jun 2010|
|Supervisor||BERNARD MASEREEL (Supervisor), Jean-Michel DOGNE (President), R. Kiss (Jury), JOHAN WOUTERS (Jury), Catherine Lambert De Rouvroit (Jury), JOHAN WOUTERS (Jury) & Jean-Yves WINUM (Jury)|
Design, synthesis molecular modelling and biological evaluation of modulators of the NF-kappa activation
Mortier, J. (Author). 7 Jun 2010
Student thesis: Doc types › Doctor of Sciences