Cot/Tpl-2 protein kinase as a target for the treatment of inflammatory disease.
Cot/Tpl-2/MAP3K8 is a serine/threonine protein kinase that is essential for lipopolysaccharide (LPS)-induced activation of the MEK/ERK pathway in macrophages as demonstrated in Cot/Tpl-2-deficient mice. Cot/Tpl-2 kinase activation plays an integral role in the production of pro-inflammatory cytokines such as TNF and IL-1beta in this immune cell type. Elevated levels of these cytokines have been clinically implicated as mediators of a number of autoimmune diseases, in particular, the pain and joint destruction of rheumatoid arthritis. By inference, pharmaceutical agents that inhibit Cot/Tpl-2 kinase have the potential to be novel and effective therapies for the treatment of these diseases. This review will describe the physiological regulation and importance of Cot/Tpl-2 in inflammation as well as the landscape of small molecules that have been reported as Cot/Tpl-2 inhibitors.
George
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Abbott Bioresearch Center, Worcester, MA 01605, USA. dawn.george@abbott.com
Salmeron
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D000893:Anti-Inflammatory Agents; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human