Kinases Raf Inhibitors - Biotech, Pharma and Life Science Channel
The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors.
Raf was the first identified and most characterized downstream effector kinase of Ras. The Raf serine threonine kinase family consists of three isoforms, Raf-1 (C-Raf), A-Raf, and B-Raf. The alternatively spliced, 94 kDa B-Raf kinase isoform is ubiquitously expressed but found mostly in testis and neuronal tissue. It is the strongest Raf kinase in terms of induction of MEK activity. Unlike Raf-1 and A-Raf, more than 30 single-site missense activating mutations occurring mostly within the B-Raf kinase domain have recently been identified in human cancers, leading to considerable excitement about B-Raf as a potential therapeutic target.
Somatic mutations of B-Raf are found in 60% of malignant melanomas and occur with moderate to high frequency in papillary thyroid carcinomas, colorectal, and ovarian cancers, strongly implicating activation of B-Raf in tumorigenesis. Preliminary evidence from Wan et al. also suggests that the presence of B-Raf mutations may determine sensitivity to drugs which target the ERK pathway at the level of Raf kinase
Several strategies have been developed that specifically target Raf kinase. These include inhibitors of Raf kinase activity such as BAY 43-9006, antisense oligonucleotides such as ISIS 5132 and LeRafAON, Raf destabilizers such as geldanamycin, and Ras-Raf interaction inhibitors such as MCP-1. Of these, only BAY 43-9006 has shown activity against B-Raf, which as discussed previously is the only Raf kinase in which activating mutations, commonly occurring in melanoma, papillary thyroid, ovarian and colon cancers, have been found.BAY 43-9006 is one of the most promising agents of the class of Raf kinase inhibitors, and has moved into phase II and III clinical trials. BAY 43-9006, is an orally available, novel bi-aryl urea compound that prevents tumor growth by combining two anticancer properties: namely, the inhibition of proliferation by targeting the ERK pathway, and the inhibition of angiogenesis by targeting the receptor tyrosine kinases VEGFR-2 and PDGFR-β and their associated signaling cascades.
Source; Mol Cancer Ther April 2005 4; 677
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Medical and Biotech [MESH] Definitions
Taxodium
A plant genus of the family TAXODIACEAE. Members contain taxodione and taxodone, which are diterpenoid quinone methide tumor inhibitors.
Huperzia
A plant genus of the family LYCOPODIACEAE. Members contain huperzine, one of the CHOLINESTERASE INHIBITORS.
Receptors, Eph Family
A large family of receptor protein-tyrosine kinases that are structurally-related. The name of this family of proteins derives from original protein Eph (now called the EPHA1 RECEPTOR), which was named after the cell line it was first discovered in: Erythropoietin-Producing human Hepatocellular carcinoma cell line. Members of this family have been implicated in regulation of cell-cell interactions involved in nervous system patterning and development.
Glycogen Synthase Kinases
A class of protein-serine-threonine kinases that was originally found as one of the three types of kinases that phosphorylate GLYCOGEN SYNTHASE. Glycogen synthase kinases along with CA(2+)-CALMODULIN DEPENDENT PROTEIN KINASES and CYCLIC AMP-DEPENDENT PROTEIN KINASES regulate glycogen synthase activity.
Proline-directed Protein Kinases
A subclass of protein serine-threonine kinases that phosphorylate proteins on a SERINE or THREONINE residue that is immediately preceding a PROLINE residue.
