Current Pharmaceutical Design - Volume 18, Issue 20, 2012

Protein kinases (PKs) play key roles in signal transduction pathways. Therefore, aberrant PK activity can cause significant alterations in many important cellular processes such as transcription, proliferation, differentiation, angiogenesis, and inhibition of apoptosis, thereby contributing to a variety of illnesses including cancer, metabolic disorders, inflammation, autoimmune diseases, diabetes, etc [1]. More than 1000 X-ray c Read More

Protein kinases are enzymes that catalyze the transfer of the γ-phosphate group from ATP to the hydroxyl groups in side chains of tyrosine, serine, or threonine. Protein kinases are divided in two classes: tyrosine kinases (TKs) and serine/threonine kinases (STKs). Overexpression or activation of protein tyrosine kinases (PTKs) has been found to be responsible for the development of many diseases, including cancer, inflammation, Read More

The vascular endothelial growth factor (VEGF) is a key regulator of neovascularization and an elevated level of VEGF is known to correlate with increased metastatic invasion. Anti-angiogenic therapies focus on targeted inhibition of overexpressed growth factors with the aim of suppressing tumor proliferation, one approach is the attempt to block the intracellular tyrosine kinase at the adenosine triphosphate (ATP) binding sit Read More

Protein kinases play central roles in cellular signaling pathways and their abnormal phosphorylation activity is inseparably linked with various human diseases. Therefore, modulation of kinase activity using potent inhibitors is an attractive strategy for the treatment of human disease. While most protein kinase inhibitors in clinical development are mainly targeted to the highly conserved ATP-binding sites and thus likely promiscuou Read More

Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by s Read More

In the last decade kinase inhibitors have emerged as a new class of very potent and relatively safe anticancer drugs. However, despite their success, off-target toxicities and induction of rapid resistance are major drawbacks that highly compromise successful longterm administration. In the current review, we provide an overview of the approaches that have been undertaken to overcome these issues by conjugation of t Read More

The insulin-like growth factors (IGF) and their receptors play pivotal roles in cellular signaling transduction and thus regulate cell growth, differentiation, apoptosis, transformation and other important physiological progresses. The insulin-like growth factor 1 receptor (IGF-1R) mainly engages in the Ras/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pat Read More

Protein kinases are potential targets of drugs to treat many human diseases. Intensive efforts have been made to develop protein kinase inhibitors, but a major challenge is achieving specificity. Exploiting regulatory elements outside the ATP binding pocket, such as the substrate binding site, may provide an alternative that allows generation of competitive inhibitors with improved selectivity. Indepth understanding of substrate reco Read More

Angiogenesis and vasculogenesis, regulated by VEGF/VEGFR signaling pathways, play key roles in tumor growth and metastasis. Selective inhibition of VEGFR kinase has been explored as a highly successful clinical strategy in cancer treatment. A number of VEGFR inhibitors have been approved in clinical use and many more are in various stages of drug development. This paper reviews selective small-molecule VEGFR inhibitors i Read More

Over the past decade, therapeutics that target subsets of the 518 human protein kinases have played a vital role in the fight against cancer. Protein kinases are typically targeted at the adenosine triphosphate (ATP) binding cleft by type I and II inhibitors, however, the high sequence and structural homology shared by protein kinases, especially at the ATP binding site, inherently leads to polypharmacology. In order to disco Read More

Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. They have been identified as being implicated in many diseases. High-resolution X-ray crystallographic data exist for many PKs and, in many cases, these structures are co-complexed with inhibitors. Although this valuable information confirms the precise structure of PKs and their complexes, it ignores the d Read More

The small GTPase RhoA and its downstream effector, Rho kinase (ROCK), appear to mediate numerous pathophysiological signals, including smooth muscle cell contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, differentiation and the expression of several genes. Clinical interest in the RhoA/ROCK pathway has increased, due to emerging evidence that this signaling pathway is involved in the Read More

Roscovitine is a synthetic inhibitor of cyclin-dependent kinases that is currently undergoing clinical trials as a candidate drug for some oncological indications. Its discovery prompted many research teams to further optimize its structure or to initiate their own related but independent studies. This article reviews known roscovitine bioisosteres that have been prepared as CDK inhibitors using different core heterocycles. The indi Read More

Thymidine kinase 2 (TK2), encoded on chromosome 16q22 of the human genome, is a deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of the pyrimidine deoxynucleosides 2’-deoxythymidine (dThd), 2’-deoxyuridine (dUrd) and 2’- deoxycytidine (dCyd) to the corresponding deoxynucleoside 5’-monophosphate derivatives. In contrast to the S-phase-specific thymidine kinase 1 (TK1), TK2 is const Read More