N, which has been linked to various cancers combined, the deregulation of the kinase activity of t over expression, as in the case of receptor and epidermal growth factor Hnlichen RTPKs. The effect of the transformation is to increased Cuscutin Bergenin Hte kinase activity t partly due to the forced dimerization, which then does not quantitatively or qualitatively different Due changed signaling cascades members, and ectopic expression of growth factors k Can to the development and maintenance of the neoplastic Ph Notyps . In particular, the expression of vascular factors was unexpected Ren endothelial growth factor and its four receptors are found on endothelial cells, play an r The major pathological situations in which neovascularization and increased Hten Gef Permeability t is concerned, such as tumor angiogenesis and lymphangiogenesis.
1.2. Selectivity of t and site targeting the discovery of therapeutic agents on the principle of kinase inhibitors is based, is not trivial. Modulate the activity t of protein kinases by low molecular weight compounds, which was the st During the binding of ligand or substrate binding to the protein or very difficult. Although the approach Bisubstrate The potential for the rational design of potent and selective inhibitors, in practice no real progress in the processing of these peptides into cells was durchl Made permeable, peptidomimetic small molecules. Similarly, generate the appropriate approach to the non-competitive or allosteric inhibitors have failed.
Although the second mechanism is new U betr Chtliche NEN attention to the development of small molecule inhibition of the binding of ligands, Src homology 2-Dom, and thus the signal-tyrosine kinase, is not, despite all efforts. Sun targeting the catalytic site of the kinase inhibitors with ATPcompetitive seems to be the most promising approach for drug action, although two large e obstacles to be overcome Access to intracellular targets and selectivity Ren t inhibition. Since there are almost 600 protein kinases, it is not surprising that the selectivity was found t, the most difficult problems of the two. The common and the diversity among the ATP-binding site of kinases for the construction of pharmacophore models for rational drug design led. Recent advances in the crystallization of protein kinases best Firmed that ATP-binding Ne of protein kinases is indeed an attractive target for drug design.
1.3. The ATP-binding site binds to the protein kinase ATP in a deep cleft between the two lobes of the protein kinase. Apart from a donor-acceptor bidentate unit Hnigen hydrogen bond in the hinge region, interactions with the nucleotide A lipophilicity / van der Waals. Although the ATP-binding site is highly conserved among protein kinases, do not have the architecture in the regions prior to the ATP-binding site, a number of important diversity. The adenine region: For practical applications in drug discovery, can be divided, the ATP binding site of protein kinases in the following main features. This hydrophobic region contains The most important two hydrogen bonds lt by the interaction of 6 N 1 and N amino groups of the adenine ring with the backbone NH groups and carbonyl Adeni trained