Current Drug Targets, Volume 4, No. 2, 2003
Contents
A Critical Analysis of New Molecular Targets
and Strategies for Drug Developments in Alzheimer's Disease Pp.97-112
Debomoy
K. Lahiri, Martin R. Farlow, Kumar Sambamurti, Nigel H. Greig, Ezio Giacobini
and Lon S. Schneider
Receptor Tyrosine Kinases: The Main Targets
for New Anticancer Therapy
Pp.113-121
Joachim
Drevs, Michael Medinger, Carmen Schmidt-Gersbach, Renate Weber and Clemens
Unger
Integrin avb3
as a Therapeutic Target for Blocking Tumor-Induced Angiogenesis Pp.123-131
3,7-Bis(dialkylamino)phenothiazin-5-ium
Derivatives: Biomedical Applications and Biological Activity Pp.133-141
J.C.V.P.
Moura, and N. Cordeiro
Regulation of Gene Expression in Vascular
Cells by Coagulation Proteins
Pp.143-158
Olga
I. Stenina
Current Targets for Anticancer Drug Discovery Pp.159-179
Fluoroquinolones: Structure and Target Sites Pp.181-190
P. G. Higgins, A. C. Fluit and F-J. Schmitz
Abstracts
[Back to top] A Critical Analysis of New Molecular Targets and
Strategies for Drug Developments in Alzheimer's Disease
Debomoy
K. Lahiri, Martin R. Farlow, Kumar Sambamurti, Nigel H. Greig, Ezio Giacobini
and Lon S. Schneider
Alzheimer’s
disease (AD), a progressive, degenerative disorder of the brain, is believed to
be the most common cause of dementia amongst the elderly. AD is characterized
by the presence of amyloid deposits and neurofibrillary tangles in the brain of
afflicted individuals. AD is associated with a loss of the presynaptic markers
of the cholinergic system in the brain areas related to memory and learning. AD
appears to have a heterogeneous etiology with a large percentage termed
sporadic AD arising from unknown causes and a smaller fraction of early onset
familial AD (FAD) caused by mutations in one of several genes, such as the b-amyloid precursor protein (APP) and
presenilins (PS1, PS2). These proteins along with tau, secretases, such as b–amyloid cleaving enzyme (BACE), and
apolipoprotein E play important roles in the pathology of AD. On therapeutic
fronts, there is significant research underway in the development of new
inhibitors for BACE, PS-1 and g-secretase
as targets for treatment of AD. There is also a remarkable advancement in
understanding the function of cholinesterase (ChE) in the brain and the use of
ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase
inhibitors is being studied and tested in human clinical trials for AD. The
development of vaccination strategies, anti-inflammatory agents,
cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of
new approaches for treating or slowing the progression of AD. In addition,
nutritional, genetic and environmental factors highlight more effective
preventive strategies for AD. Developments of early diagnostic tools and of
quantitative markers are critical to better follow the course of the disease
and to evaluate different therapeutic strategies. In this review, we attempt to
critically examine recent trends in AD research from molecular, genetic to
clinical areas. We discuss various neurobiological mechanisms that provide the
basis of new targets for AD drug development. All these current research
efforts should lead to a deeper understanding of the pathobiochemical processes
that occur in the AD brain in order to effectively diagnose and prevent their
occurrence.
[Back to top] Receptor Tyrosine Kinases: The Main Targets
for New Anticancer Therapy
Joachim
Drevs, Michael Medinger, Carmen Schmidt-Gersbach, Renate Weber and Clemens
Unger
Because
conventional chemotherapy is not specific for cancer cells leading to toxic
side effects there is a need for novel agents with high grade antitumor
specificity. The major prerequisite to develop such drugs is to understand the
targets that these agents should attack. In recent years a number of promising
new anticancer drugs have been developed which target intracellular pathways or
extracellular cell molecules. The clinically most effective compounds function
as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors
have been identified as regulators of tumor or tumor vessel growth. Having
shown their expression characteristics in different tumor entities, specific
inhibitors of the ATP binding sites of these receptors or antibodies were
developed and entered clinical trials. The pathognomonic role of the tyrosine
kinase defines the way of action of the inhibiting drug, whereas the amount of
expression in tumor tissue defines the rationale to use the inhibitor to treat
a specific protein. The future will define indications for such drugs by tumor
kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL
tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase;
Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584,
inhibiting the VEGF-receptor tyrosine kinase will be discussed as
representatives of selective tyrosine kinase inhibitors whereas ZD6474 and
SU6668 will be discussed as representatives of multitarget tyrosine kinase
inhibitors.
[Back to top] Integrin avb3
as a Therapeutic Target for Blocking Tumor-Induced Angiogenesis
C.
Chandra Kumar
The integrin
receptor avb3 has been
shown to play a critical role in several distinct processes, such as
angiogenesis, osteoclast-mediated bone resorption and tumor metastasis. Its
expression is upregulated in newly synthesized blood vessels produced in
response to a variety of tumors and purified angiogenic factors. Studies show that
avb3 is a
critical target downstream from perhaps all angiogenic factors.
Proof-of-principle that avb3 antagonists such as monoclonal antibodies
and small molecules block angiogenesis and tumor growth has been obtained in
several animal models. Many endogenous inhibitors of angiogenesis such as
angiostatin, endostatin and tumstatin seem to work through the avb3 receptor
further emphasizing the critical role of this receptor in angiogenesis. In
addition, the avb3 receptor
has been clearly implicated in several pathological processes such as
rheumatoid arthritis, osteoporosis, and metastasis of prostate cancer to bone.
Thus avb3 may prove
to be an important target for pharmacological intervention in more than one
clinical setting.
[Back to top] 3,7-Bis(dialkylamino)phenothiazin-5-ium
Derivatives: Biomedical Applications and Biological Activity
J.C.V.P.
Moura, and N. Cordeiro
The light-induced
reactions of 3,7-bis(dialkylamino)phenothiazin-5-ium compounds with biological
substrates are briefly discussed. Their biomedical applications, in particular
those related with biological staining, interaction with proteins and
antiviral, antibacterial and antitumour activity are reviewed.
[Back to top] Regulation of Gene Expression in Vascular Cells by Coagulation
Proteins
Olga
I. Stenina
Receptors of
vascular cells and coagulation proteins form a tightly integrated and balanced
system, providing regulation to coagulation and mediating a response to coagulation
by the vascular cells. Endothelial and smooth muscle cells express a variety of
proteins directly participating in hemostasis. Engagement of activated
coagulation proteins by their specific receptors on the vascular cell surface,
in turn, activates these cells and leads to expression of genes involved in
coagulation, angiogenesis, leukocyte adhesion, regulation of the vascular wall
tone, etc. The signals inducing the expression of target genes are mediated by
protease-activated receptors, which are shared among coagulation proteases.
However, differences in mechanisms of activation of these receptors, as well as
the presence of specific receptors for each coagulation protein and structures
of promoters of target genes, may provide specificity in the responses of
vascular cell types to different coagulation factors. Activation of gene
expression in vascular cells by coagulation proteases accounts for the
long-term consequences of coagulation in disorders such as atherosclerotic
lesion development, cancer growth, and inflammation. Multiple intracellular
pathways and specific trancsriptional mechanisms activated by coagulation
proteins represent an attractive target for drug design, providing the
possibility of controlling the adverse effects of coagulation activation
without interfering with the hemostatic requirements of coagulation.
This review
discusses regulation of gene expression in vascular cells by thrombin, tissue
factor, factor VIIa, factor Xa and protein C. Differences and similarities in
mechanisms of receptor activation, the pathological profiles of genes activated
by these coagulation factors, and recently described transcriptional mechanisms
that they induce are discussed.
[Back to top] Current Targets for Anticancer Drug Discovery
Nguyen-Hai
Nam ,and Keykavous Parang
The call for the
discovery of less toxic, more selective, and more effective agents to treat
cancer has become more urgent. Inhibition of angiogenesis continues to be one
of the main streams in the current cancer drug discovery activity. Insights
into tumor angiogenesis biology have led to the identification of a number of
molecules, which are important for the progression of these processes. Of
particular interest is a group of growth factors including fibroblast growth
factor, platelet-derived growth factor, and vascular endothelial growth factor.
These growth factors and their corresponding receptor tyrosine kinases have
become important targets for inhibition of the proliferation of endothelial
cells, the main component of blood vessels. The validated targets for
inhibition of angiogenesis also include a family of matrix metalloproteinases
and cell adhesion molecules. In the closely related area, protein kinases have
emerged as one of the most important targets for drug discovery. Besides growth
factor receptor tyrosine kinases, numerous other protein kinases implicated in
malignancies have been identified including non-receptor kinases such as
Bcl-Abl and Src kinases. In addition, the cell cycle regulators
(cyclin-dependent kinases, p21 gene) and apoptosis modulators (Bcl-2
oncoprotein, p53 tumor suppressor gene, survivin protein, etc) have also
attracted renewed interest as potential targets for anticancer drug discovery.
Other molecular targets include protein farnesyltransferase (FTase), histone
deacetylase (HDAC), and telomerase, which have essential roles in cellular
signal transduction pathways (FTase, HDAC) and cell life-span (telomerase).
This review presents a comprehensive summary and discussion on the most
important targets currently attracting a great deal of interest in contemporary
anticancer drug design and discovery. Recent advances complementing these
targets are also highlighted.
[Back to top] Fluoroquinolones: Structure and Target Sites
P. G. Higgins, A. C. Fluit and F-J. Schmitz
The quinolones are
a potent group of drugs that target the essential bacterial enzymes DNA gyrase
and topoisomerase IV. DNA gyrase is the primary target of Gram negative
organisms however, it is topoisomerase IV that is the primary target of Gram
positive organisms. Within these enzymes is a highly conserved region centered
round the active site where resistance mutations occur. These mutations are
almost always identical, irrespective of organism. In spite of the homology of
this region, amino acid sequence analysis shows that there are defined
differences between the Gram groups, particularly in topoisomerase IV, and it
is speculated that herein lies the origin of target preference.
Since the first
quinolone nalidixic acid was developed, the quinolones have undergone
structural modifications, in particular the addition of a fluorine at position
6, to produce the fluoroquinolones. This has seen their potency and
pharmakokinetic profile greatly increase. In vitro selection of resistance
mutations has allowed the observation of how resistance is acquired and some of
the modifications in newer fluoroquinolones have resulted in the shift of
primary target from topoisomerase IV to gyrase with Gram positives. Curiously,
purified topoisomerase IV is still more sensitive even if gyrase is the primary
target. Gyrase remains the primary target for Gram negatives.