Current Topics in Medicinal Chemistry - Volume 9, Issue 7, 2009

A variety of chronic inflammatory and immune-mediated diseases cause undue patient pain and suffering, and represent significant areas of unmet medical need. Rheumatoid arthritis is a chronic systemic inflammatory disorder which affects almost one percent of the world's population, and its long-term treatment is underserved by existing disease-modifying antirheumatic drugs. Chronic obstructive pulmonary disease, charact Read More

FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is overexpressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as w Read More

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 Read More

The IκB kinases (IKKs) are essential components of the signaling pathway by which the NF-κB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFα). NF-κB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders i Read More

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 η, has become a focus of research. PKCθ, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. Read More

Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revol Read More