Cot/Tpl-2 Protein Kinase as a Target for the Treatment of Inflammatory Disease

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Abstract:

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-1β 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.

Keywords: Cot/Tpl-2; LPS; kinase inhibitors; macrophages; serine/threonine kinase

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/156802609789007345

Affiliations: Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.

Publication date: May 1, 2009

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