Raf Kinase Inhibitors
Raf kinases are a group of serine/threonine kinases that include A-Raf, B-Raf, and c-Raf1. A-Raf is abundant in urogenital tissues, B-Raf is predominantly expressed in neural tissue, and c-Raf1 is ubiquitous in its distribution. Raf kinases play an important role as extracellular signal-regulating kinases in cell differentiation, proliferation, and apoptosis. The three Raf proteins share a common structure consisting of an N-terminal regulatory domain and a C-terminal kinase domain. Each Raf has three conserved regions, CR1, CR2, and CR3. In the regulatory domain, CR1 contains a Ras-binding domain and a cysteinerich domain, CR2 is a serine/threonine-rich domain, and CR3 contains the kinase domain and is essential for Raf activity. The removal of the regulatory domain generates an oncogenic kinase.
All three Raf proteins also share common mechanisms of activation and downstream effectors. They work at the entry point of the mitogen-activated protein kinase/extracellularsignal- regulated kinase (MAPK/ERK) pathway, a signaling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. They serve as downstream effectors of Ras signaling; however, the interaction between Ras and Raf alone is not sufficient for full activation of Raf kinases. Additional proteins and enzymes are required for full activation. 14-3-3 proteins are known to bind directly to Raf and their binding to Ser621 of Raf-1 is essential to keep Raf in an inactive, but activation-competent confirmation. PKA is reported to phosphorylate Ser43 and Ser621 and prevent the activation of Raf1. Inhibition of PKA has been linked to the growth factorinduced activation of c-Raf1. Ser728 in the 14-3-3 binding region in B-Raf is also known to be a target for PKA phosphorylation.
Abnormal activation of Raf signaling pathway is common in several type of cancers. Hence, there is a significant interest in the development of specific inhibitors that may reverse the progression of these tumors. These inhibitors may block the expression of Raf protein, block its interaction with Ras, or block its kinase activity. More recently, c-Raf inhibitors have been considered as protective agents against Β-amyloid toxicity.
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Kolch, W., et al. 2002. Expert Rev. Mol. Med. 25, 1.
