Current Topics in Medicinal Chemistry - Volume 9, Issue 8, 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

Activation of the extracellular signal-regulated kinase (ERK) signaling pathway has been implicated in mediating a diverse array of cellular functions including cell differentiation, proliferation, and inflammatory responses. In this review, we will discuss approaches to identify inhibitors of ERK proteins through targeting ATP-dependent and ATPindependent mechanisms. Given the diversity of ERK substrates and the importance Read More

Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4, and FcηR-mediated signaling pathways. In T cells, ITK is an important mediator for actin reorganization, activation of PLCγ, mobilization of calcium, and activation of the NFAT transcription factor. ITK plays a Read More

Inhibitors of Rho kinase (ROCK) have many potential therapeutic applications. The biological focus of this overview will be on the role of ROCK in inflammatory disorders such as multiple sclerosis and asthma. Many ROCK inhibitors have been described in the primary and patent literature, and a diverse range of chemical scaffolds is beginning to emerge. Some of the structural classes that will be highlighted in this review includ Read More

Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have b Read More

In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kδ) and gamma (PI3Kγ) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (α/β/γ/δ) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K δ/γ lipid kinases are mainly restrict Read More