Abstract
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.
MeSH terms
-
Animals
-
Arthritis, Rheumatoid / drug therapy
-
Chemistry, Pharmaceutical / methods
-
Drug Design
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / pharmacology*
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Humans
-
Hydrogen Bonding
-
Inhibitory Concentration 50
-
Interleukin-1beta / metabolism
-
Ligands
-
MAP Kinase Kinase Kinases / antagonists & inhibitors*
-
MAP Kinase Kinase Kinases / chemistry
-
Mice
-
Molecular Structure
-
Proto-Oncogene Proteins / antagonists & inhibitors*
-
Proto-Oncogene Proteins / chemistry
-
Pyridines / chemical synthesis*
-
Pyridines / pharmacology
-
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
-
Tumor Necrosis Factor-alpha / chemistry
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Enzyme Inhibitors
-
Interleukin-1beta
-
Ligands
-
Proto-Oncogene Proteins
-
Pyridines
-
Tumor Necrosis Factor-alpha
-
thienopyridine
-
Extracellular Signal-Regulated MAP Kinases
-
MAP Kinase Kinase Kinases
-
MAP3K8 protein, human