Current Medicinal Chemistry - Volume 18, Issue 19, 2011

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 i Read More

Tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs, essentially because many kinases and regulators are molecules related to frequently mutated oncogenes and tumor suppressors. Many experiments and clinical data in different tumors show that better cancer therapy can be obtained by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets Read More

Protein phosphorylation is one of the major pathways used by eukaryotic cells to propagate signals to the final effectors, regulating multiple aspects of the living cell, such as metabolism, growth, differentiation, adhesion, motility, genome stability and death. In this context, tyrosine kinases (TKs) play a central role in signal transduction and their overexpression or disregulated activity has been implicated in tumor onset and malig Read More

Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families, and knowledge of their three-dimensional structure could be of great help in the rational design of specific ligands. However, only about one quarter of human protein kinase structures has been experimentally defined; thus, kinase homology modeling techniques have been widely diffused. In thi Read More

Cell cycle regulation involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control cell cycle are ordered and directional. Cyclins and cyclin-dependent kinases (CDKs), determine cell progression through the cycle ensuring the orderly coordination of cellular events. Alterations of cell cycl Read More

Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic and essential protein kinase whose abnormally high constitutive activity has been implicated in several human diseases. In the last decade, several ATP competitive inhibitors of CK2, characterized by an in vitro activity that ranges from micromolar to nanomolar, have been discovered. However, until now only one drug candidate has been entered in Phase I clinical trial a Read More

The tumor microenvironment is characterized, not only by marked gradients in drug concentration, but also by gradients in the rate of cell proliferation and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Hypoxia is also an important environmental factor in chronic myeloid leukemia (CML), because bone marrow is intrinsically hypoxic in nature. Systems-wide analyses Read More

Kit is a growth factor receptor of the type III tyrosine kinase family, whose gain-of-function mutations have been identified as driving causes of different kinds of tumours. It thus represents a viable drug target, and the development of Kit inhibitors has been shown to be a promising therapeutic concept. This review will focus on structural and signalling properties of both wild-type and mutant Kit, as well as its role in t Read More

The central events of HIV-1 life cycle occur at the nuclear level where the viral genome is integrated into the host cellular DNA in order to be expressed and replicated. The viral pre-integration complexes (PICs) are actively transported in the nuclear compartment where integration occurs in specific regions of the cellular chromatin. Similar to all viruses, HIV-1 encodes for a limited number of proteins that are insufficient to Read More

Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signalling associated with receptor Read More

Fyn is a non-receptor tyrosine kinase belonging to the Src family kinases. It has been shown to play important roles in neuronal functions, including myelination and oligodendrocytes formation, and in inflammatory processes. It has also demonstrated its involvement in signaling pathways that lead to severe brain pathologies, such as Alzheimer's and Parkinson's diseases. Moreover, Fyn is upregulated in some malignancies. Exp Read More

Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia-positive (Ph+) CML in the chronic Read More

The mammalian target of rapamycin (mTOR) is frequently activated in epithelial ovarian cancer, and is regarded as an attractive therapeutic target for therapy. Preclinical investigations using rapamycin and its analogs have demonstrated significant growthinhibitory effects on the growth of ovarian cancer both in the setting of monotherapy and in combination with cytotoxic agents. Based on promising preclinical data, mTOR Read More

The worldwide dissemination of «multi-drug resistant» (MDR) pathogens has severely reduced the efficacy of our antibiotic arsenal and increased the frequency of therapeutic failure. MDR bacteria over-express efflux pumps and this active mechanism can extrude all classes of antibiotics from the cell. It is necessary to clearly decipher the genetic, structural and functional aspects of this transport system in order to combat this Read More