Progress towards the development of anti-inflammatory inhibitors of IKKbeta.
The IkappaB kinases (IKKs) are essential components of the signaling pathway by which the NF-kappaB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFalpha). NF-kappaB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders including rheumatoid arthritis (RA), chronic obstructive pulmonary disorder (COPD), and asthma. Inhibition of the kinase activity of the IKKs is therefore a promising mechanism for intervention in these diseases. Here, we will review the literature describing small molecule inhibitors of IKKbeta (IKK2), the most widely studied of the IKKs.
Bamborough
Paul
P
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.A.Bamborough@gsk.com
Callahan
James F
JF
Christopher
John A
JA
Kerns
Jeffrey K
JK
Liddle
John
J
Miller
David D
DD
Morse
Mary A
MA
Rumsey
William L
WL
Williamson
Rick
R
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D054852:Small Molecule Libraries
D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D051550:I-kappa B Kinase