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Protein kinases
Protein kinases (PKs) are important mediators of normal cellular signal transduction. By adding phosphate groups to substrate proteins, they direct the activity, localization and overall function of many proteins, and serve to orchestrate the activity of almost all cellular processes. Protein kinases play a key role in virtually all physiological processes including proliferation, angiogenesis, migration, cell cycle, etc. The diversity of essential functions mediated by kinases is shown by the conservation of more than 50 distinct kinase families between yeast, invertebrate and mammalian kinomes. Of the 518 human protein kinases, 478 belong to a single superfamily whose catalytic domains are related in sequence. It is now recognized that abnormal phosphorylation of proteins mediated by kinases may result in diseases including cancer, diabetes,rheumatoid arthritis and hypertension, arteriosclerosis, psoriasis, and a large number of inflammatory responses . The development of specific PK inhibitors as pharmacological tools and potential antiproliferative agents is an active and highly competitive area of research. The phylogenetic trees of the PK families, subfamilies and groups can be identified from the several databases . Despite extensive efforts of pharmaceutical companies and academic groups, there are only a few small molecule inhibitors of protein kinases widely available as drugs. The reason for the scarcity of PK-targeted drugs is the stringent criteria
required for a therapeutically useful small molecule inhibitor of these enzymes. Inhibitors need to be highly potent, selective among the closely related enzymes, and also possess adequate pharmacodynamic properties for the target of interest.
Protein kinases can be clustered into several distinct groups, families and sub-families, of increasing sequence similarity and biochemical function. The kinase dendrogram shows the sequence similarity between these catalytic domains: the distance along the branches between two kinases is proportional to the divergence between their sequences. Seven major groups are labeled and colored
distinctly. For instance, the tyrosine kinases (TKs) form a distinct group, whose members phosphorylate proteins on tyrosine residues, whereas enzymes in all other groups phosphorylate primarily serine and threonine residues.
Protein kinase inhibitors represent an important and still emerging class of targeted therapeutic agents.Drug discovery and development strategies have explored numerous approaches to target the inhibition of protein kinase signaling.
Tyrosine kinase family
Among the PTs discovered to date tyrosine kinases seem to be the most attractive biological targetsfor cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. In addition, they play a critical role in other diseases, for example in inflammation and rheumatoid arthritis .
Tyrosine kinases are known as key switches in many cellular signal transduction pathways and catalyze transfer of ATP γ-phosphate onto a protein substrate. Although tyrosine kinases vary in size,mechanism of activation, subunit composition, and subcellular localization, they all share a structurally conserved ATP binding catalytic core, the main binding site for most of TK inhibitors. The conservednature of this binding site represents a challenge for the selection of inhibitors. Most of TK ligands share specific steric, lipophilic, H-binding, and other parameters. The combination of these physico-chemical properties constitutes the basis for a statistical model discriminating between TK ligands and non-TK-active agents.
A large sub-family of TKs includes many groups which can be divided in two major classes in accordance to their localization and specificity: receptor tyrosine kinases and non-receptor (cytoplasmatic) tyrosine kinases
For example, three tyrosine kinase families, the Src, Tec and Syk kinase families are intimatelyinvolved in TLR signalling, the critical first step in cellular recognition of invading pathogens and tissue damage. Their activity results in changes in gene expression in affected cells. Key amongst these genes are the cytokines, which orchestrate both the duration and extent of inflammation. Tyrosine kinases also play important roles in cytokine function, and are implicated in signalling through both pro- and antiinflammatory cytokines such as TNF, IL-6 and IL-10.
Among various groups of TKs, abl-kinase and grow-factor receptor tyrosine kinases, especially FGFR, EGFR, VGFR and IGF1R kinases, are the most promising targets particularly implicated in cancer grow and progression. Thus, constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase’s activity led to novel cancer therapy using TKs blockers. These drugs are
remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate,Gleevec, STI571), the inhibitor of bcr/abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for abl non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase,AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay
43-9006, Nexavar), and Leflunomide (SU101, Arava). In accordance with the examples just above, efficient tools are needed for the high-throughput search for novel candidates to be assayed as TK-targeted drugs. The key to harnessing the high therapeutic potential of TKs is in the design of high-quality small molecule libraries targeted against these proteins.
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