Novel IKK inhibitors: beta-carbolines.
Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.
Castro
Alfredo C
AC
Millennium Pharmaceuticals Inc., 35 Landsdowne Street, 02139, Cambridge, MA, USA.
Dang
Luan C
LC
Soucy
François
F
Grenier
Louis
L
Mazdiyasni
Hormoz
H
Hottelet
Maria
M
Parent
Lana
L
Pien
Christine
C
Palombella
Vito
V
Adams
Julian
J
D015153:Blotting, Western; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002243:Carbolines; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human