Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1.
IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).
Murata
Toshiki
T
Department of Chemistry, Research Center Kyoto, Bayer Yakuhin, Ltd., Kizu, Soraku, Kyoto 619-0216, Japan. toshiki.murata.tm@bayer.co.jp
Shimada
Mitsuyuki
M
Sakakibara
Sachiko
S
Yoshino
Takashi
T
Kadono
Hiroshi
H
Masuda
Tsutomu
T
Shimazaki
Makoto
M
Shintani
Takuya
T
Fuchikami
Kinji
K
Sakai
Katsuya
K
Inbe
Hisayo
H
Takeshita
Keisuke
K
Niki
Toshiro
T
Umeda
Masaomi
M
Bacon
Kevin B
KB
Ziegelbauer
Karl B
KB
Lowinger
Timothy B
TB
D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000032:analysis; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D020128:Inhibitory Concentration 50; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse