Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production.
COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
Cusack
Kevin
K
Abbott Laboratories, Medicinal Chemistry, 100 Research Drive, Worcester, MA 01605, USA.
Allen
Hamish
H
Bischoff
Agnieszka
A
Clabbers
Anca
A
Dixon
Richard
R
Fix-Stenzel
Shannon
S
Friedman
Michael
M
Gaumont
Yvette
Y
George
Dawn
D
Gordon
Thomas
T
Grongsaard
Pintipa
P
Janssen
Bernd
B
Jia
Yong
Y
Moskey
Maria
M
Quinn
Christopher
C
Salmeron
Andres
A
Thomas
Christine
C
Wallace
Grier
G
Wishart
Neil
N
Yu
Zhengtian
Z
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D008024:Ligands; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C446540:thienopyridine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human