Abstract
Our efforts to develop raf kinase inhibitors derive from the clear, causal role of Ras proteins in human cancer, and the understanding that raf kinase is a direct downstream effector of Ras action. K-ras is activated by mutation in more than 20% of all solid tumors, N-ras in 30% of leukemias and lymphomas, and H-ras in small numbers of solid and liquid tumors. In addition, normal Ras alleles are frequently amplified in human tumors, and pathways upstream of Ras are amplified (HER2/neu, for example) or activated by gene rearrangement (bcr-abl) or mutation such as epidermal growth factor (EGF)-receptor in glioblastoma, for example. For these reasons, Ras has long been considered a promising target for therapeutic intervention (reviewed in 1).
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References
McCormick F. Small-molecule inhibitors of cell signaling. Curr Opin Biotechnol 2000;11:593–597.
Feramisco JR, Clark R, Wong G, et al. Transient reversion of ras oncogene-induced cell transformation by antibodies specific for amino acid 12 of ras protein. Nature 1985;314:639–642.
Wittinghofer A, Franken SM, Scheidig AJ, et al. Threedimensional structure and properties of wild-type and mutant H-ras-encoded p21. Ciba Found Symp 1993;176:6–21.
Ahmadian MR, Zor T, Vogt D, et al. Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proc Natl Acad Sci USA 1999;96:7065–7070.
Prendergast GC, Rane N. Farnesyltransferase inhibitors: mechanism and applications. Expert Opin Investig Drugs 2001;10:2105–2116.
Van Aelst L, Barr M, Marcus S, et al. Complex formation between RAS and RAF and other protein kinases. Proc Nall Acad Sci USA 1993;90:6213–6217.
Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000;351:289–305.
Freed E, Symons M., Macdonald SG, et al. Binding of 14–3–3 proteins to the protein kinase Raf and effects on its activation. Science 1994;265:1713–1716.
Stokoe D, McCormick F. Activation of c-Raf-1 by Ras and Src through different mechanisms: activation in vivo and in vitro. EMBO J 1997;16:2384–2396.
Shimizu K, Ohtsuka T, Takai Y. Cell-free assay system for Ras- and Rap 1-dependent activation of MAP-kinase cascade. Methods Mol Biol 1998;84:173–183.
Hamad NM, Elconin JH, Karnoub AE, et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 2002;16:2045–2057.
Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411:1017–1021.
Diehl JA, Cheng M, Roussel MF, et al. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998;12:3499–3511.
Ries SJ, Biederer C, Woods D, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p 14ARF. Cell 2000;103:321–330.
Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001;98:11,
Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001;98: 598–11,
Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001;98:603.
Davies H, Bignell Gr, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954.
Ikeda T, Yochinaga K, Suzuki A, et al. Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer. Oncol Rep 2000;7:567–570.
Tsao H, Zhang X, Fowlkes K, et al. Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res 2000;60:1800–1804.
Macdonald SG, Crews CM, Wu L, et al. Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. Mol Cell Biol 1993;13:6615–6620.
Lyons JF, Wilhelm S, Hibner B, et al. Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 2001;8:219–225.
Lowinger TB, Riedl B, Dumas J, et al. Design and discovery of small molecules targeting raf-1 kinase. Curr Pharm Des 2002;8:2269–2278.
Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999;5:810–816.
Wilhelm S, Chien DS. BAY 43–9006: preclinical data. Curr Pharm Des 2002;8:2255–2257.
Hotte SJ, Hirte HW. BAY 43–9006: early clinical data in patients with advanced solid malignancies. Curr Pharm Des 2002;8:2249–2253.
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McCormick, F. (2004). Development of an Inhibitor of raf Kinase. In: Kelloff, G.J., Hawk, E.T., Sigman, C.C. (eds) Cancer Chemoprevention. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-767-3_26
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DOI: https://doi.org/10.1007/978-1-59259-767-3_26
Publisher Name: Humana Press, Totowa, NJ
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