Pyrazolo[4,3-c]isoquinolines as potential inhibitors of NF-kappaB activation.
In this work, 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-kappaB pathway.
Mortier
Jérémie
J
Drug Design & Discovery Center, University of Namur, FUNDP, Belgium.
Frederick
Raphaël
R
Ganeff
Corinne
C
Remouchamps
Caroline
C
Talaga
Patrice
P
Pochet
Lionel
L
Wouters
Johan
J
Piette
Jacques
J
Dejardin
Emmanuel
E
Masereel
Bernard
B
D001172:Arthritis, Rheumatoid / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000037:antagonists & inhibitors*; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011720:Pyrazoles / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
D007546:Isoquinolines; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011720:Pyrazoles; D011994:Recombinant Proteins; D000099151:MAP Kinase Kinase Kinase 7