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Editorial [Hot Topic: Protein Kinases in Cancer: Recent Findings (Guest Editor: Silvia Schenone)]

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Protein kinases are responsible for key events in the cells, and their hyperactivation, overexpression or mutations have been detected in several human cancers. Kinase inhibitors are currently one of the most important classes of anticancer drugs, and both one-target-selective and dual or politargeted compounds have been approved for therapy of haematological or solid malignancies in the last decade, representing new important tools for the fight against cancer.

Inhibition of a single kinase (Bcr-Abl in chronic myeloid leukemia and Kit in gastrointestinal stromal tumors) led to the discovery of fundamental drugs, such as imatinib, that can cure these diseases. However several cases of drug resistance have been reported and prompted the search for new compounds able to act on mutated enzymes and/or in the real tumor microenvironment that is characterized by marked gradients in drug concentration and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment.

Moreover systems-wide analyses of tumors have recently identified receptor tyrosine kinase (RTK) coactivation as an important mechanism by which cancer cells achieve chemoresistance and for this reason also the research of multitargeted kinase inhibitors that might target both receptor and cytoplasmatic kinases, is very active. Indeed experiments and clinical data in different tumors show that a better cancer therapy can be obtained with a polypharmacology approach, by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets and adjusting drug dosages for the best results.

A great debate also exists whether to use peptides or small molecules, being the field of cyclin-dependent kinases (CDKs) an important example. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site.

Kinases are also involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle.

Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches.

The ever-deepening study of kinome addressed the interest also in kinases not yet targeted until now for the synthesis of potential drugs, such as protein kinase CK2, an ubiquitous and constitutively active protein kinase, that catalyzes the phosphorylation of more than 300 substrates or two other cytoplasmatic kinases, Fes and Fyn, both involved in cancer development and the latter also in CNS degenerative pathologies, such as Alzheimer's disease.

The common problems faced by the antiviral and anticancer fields needs the integration of structural, biochemical and in silico modelling approaches for the development of novel highly active kinase inhibitors. Particularly the knowledge of protein kinase three-dimensional structure is of great help in the rational design of specific ligands and kinase homology modeling techniques have been widely diffused.

The research in the field of kinase inhibition is extremely active, also due the high number of protein kinases identified, as evidenced by the increasing number of publications that appear in the literature daily. For these reasons new updates are always needed and in this special issue some of the most exciting studies on this topic are reported.
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Document Type: Research Article

Publication date: 2011-06-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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