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Small Molecule Inhibitors of PKCθ as Potential Antiinflammatory Therapeutics

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Members of the protein kinase C (PKC) family of serine/threonine kinases have been targeted for drug discovery for over 20 years, initially focusing on inhibitors of the classic PKCs, which include the α, β, and γ isoforms. Recently, inhibition of the activity of the novel PKC isoforms, namely θ, δ, η, and , has become a focus of research. PKCθ, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. While T cells play critical roles in initiating and controlling the immune response, inappropriate or extended stimulation of T cells is responsible for many chronic inflammatory diseases. Mice with an engineered deficiency in PKCθ have reduced incidence and severity of several inflammatory disorders including asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and allograft rejection. This review summarizes the efforts directed towards the design of small molecule PKCθ inhibitors as potential therapeutic agents.

Keywords: PKCθ; Protein kinase C; inflammatory disease

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/156802609789007372

Affiliations: Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965.

Publication date: May 1, 2009

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