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Current
Signal Transduction Therapy
ISSN: 1574-3624
Current Signal
Transduction Therapy
Volume 1, Number 1, January 2006
Contents
Editorial
[Editorial
IN PDF]
Signal Transduction Therapy for Cancer – Whither Now?
Pp. 1-12
Shoshana Klein and Alexander Levitzki
[Abstract] [Full
Text Article]
Design and Development of Signal Transduction Inhibitors for
Cancer Treatment: Experience and Challenges with Kinase Targets
Pp. 13-23
Ian Collins and Paul Workman
[Abstract] [Full
Text Article]
Nuclear Factor-κB: A Holy Grail in Cancer Prevention
and Therapy Pp. 25-52
Bharat B. Aggarwal, Gautam Sethi, Asha Nair and Haruyo
Ichikawa
[Abstract] [Full
Text Article]
Epithelial Cell Signaling in Helicobacter pylori Infection
Pp. 53-65
Jean E. Crabtree and Michael Naumann
[Abstract] [Full
Text Article]
Signal Transduction Therapy with Rationally Designed
Kinase Inhibitors Pp. 67-95
György Kéri, László O"rfi,
Dániel Ero"s, Bálint Hegymegi-Barakonyi,
Csaba Szántai-Kis, Zoltán Horváth, Frigyes
Wáczek, Jen o" Marosfalvi, István Szabadkai,
János Pató, Zoltán Greff, Doris Hafenbradl,Henrik
Daub, Gerhard Müller, Bert Klebl and Axel Ullrich
[Abstract] [Full
Text Article]
Polypeptide and Protein Aggregates with Neurotoxic
Properties in Neuro-degenerative Disorders: Emphasis on β-Amyloid-Induced
Dysfunction of Receptor-Mediated Signal Transduction Pathways
Pp. 97-112
Yann Verdier and Botond Penke
[Abstract] [Full
Text Article]
Molecular Targeting of Cell Death Signal Transduction
Pathways in Cancer Pp. 113-131
Istvan Petak, Janet A. Houghton and Laszlo Kopper
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
[Editorial
IN PDF]
”Sickness comes from lost integrity Sickness comes
from lack of inner peace The unity of spirit, soul, body and
mind Will make You happy and shine” (Taoist poem)
In the last years signal transduction therapy has become
one of the most important area of modern drug research. It
has become evident that, in most of our diseases, intra-or
intercellular communication disorders are in the background
of the complex pathomechanisms. Current Signal Transduction
Therapy (CSTT) is aimed to provide a broad overview with in-depth
reviews as well as original papers about signaling related
molecular pathomechanisms and the potential therapeutic strategies.
This is a new journal in the very successful Current series
published by Bentham Science Publishers.
In the pathological states with signaling disorders a series
of genomic changes can be the cause and the consequence of
these cell-communication problems. In a healthy organism,
normal cells fulfill their duties, do not send or receive
false messages and are strongly controlled by the external
messages of the communication network. On the other hand,
for example, cancer cells generate a false, mimicked proliferation
signal for themselves via oncogenes and other genomic changes.
Whether this communication failure is the result of environmental
factors and/or external messages (generating changes at the
genomic level), or originates in the genetic program is still
a question, and can be answered only on a case-by-case basis.
However we have to consider that cells, like human beings,
live in a well organized society and in a given ecosystem,
which, to a certain extent, determines their receptivity and
responsiveness in addition to the systemic response for the
various carcinogenic agents and effects.
In the molecular pathomechanism of various diseases certain
changes at the genomic level are critical steps, however the
manifestation of these genomic changes and the system response
depends very much on the communication state and responsibility
of the system. The processes of cellular growth and differentiation
as well as the maintenance of specialized functions show a
remarkable degree of coordination and it has been clearly
demonstrated that this involves intercellular communication,
rather then relying entirely on intracellular programming.
In the pathological state, the normally interdependent system
controls are uncoupled and certain cellular functions or malfunctions
are stimulated in such a way as to result in further damage-causing
signals, or often in the growth of the malfunctioning cells.
Proliferation of infected, damaged or malfunctioning cells
is very often a key factor in the generation of the pathological
state, not only in cancer and infectious diseases but also
in inflammation or autoimmune-related diseases like arteriosclerosis,
arthritis, or certain inflammation-related neurodegenerative
diseases.
Disease manifestation starts when these malfunctioning or
transformed cells diversify, and variants with altered properties
arise in the population. To survive and function in a competitive
environment, such variants must have selective growth and
communicative properties and other competitive advantages
over other cells. The surviving malfunctioning cells must
have specific signal transduction pathways turned on, with
these all the feedback effects and inhibitory actions of the
micro environmental parameters cannot interfere. Since most
of the recently identified validated target molecules of drug
research are signal transduction related macromolecules, most
of the pathomechanisms and drug research areas relate to signal
transduction therapy.
We trust that CSTT will be a unique journal which could provide
scientists with very useful information about molecular pathomechanisms,
intra and intercellular signaling, target molecules, therapeutic
strategies and drug discovery. For the first issue several
well known experts of the field contribute very important
papers and reviews about Signal Transduction Therapy achievements,
modulating the kinome for molecular cancer therapy, rational
drug design of kinase inhibitors, NF-KAPPA B signaling, signaling
in Helicobacter pylori infection, cell death signal
transduction pathways, and signaling disturbances in Alzheimer's
disease.
György Kéri and Axel Ullrich
Co-Editors in Chief
[Back to top]
Signal Transduction Therapy for Cancer – Whither
Now?
Shoshana Klein and Alexander Levitzki
[Full Text Article]
Signal transduction therapy for cancer targets pathways
that are over-active in cancer cells and upon which the cancer
cells depend for their survival. Protein kinases are prime
targets for signal transduction therapy. A major breakthrough
was the introduction of the Bcr-Abl inhibitor imatinib/Gleevec
into the clinic for the treatment of chronic myelogenous leukemia
(CML). Nevertheless, even for this clonal disease, which has
a well-characterized principle survival factor, signal transduction
therapy faces two major problems: the emergence of drug-resistant
clones and the persistence of a small population of cancer
stem cells that re-establish the leukemia if treatment is
stopped. Most cancers are far more heterogeneous than CML,
so choosing the appropriate molecular targets is a major challenge.
Signal transduction therapy can potentially reduce tumor mass
and control cancer as a chronic disease. Complete cures will
require ways of combating cancer stem cells and preventing
metastasis, such as harnessing bystander effects and the immune
system during treatment.
[Back to top]
Design and Development of Signal Transduction Inhibitors
for Cancer Treatment: Experience and Challenges with Kinase
Targets
Ian Collins and Paul Workman
[Full Text Article]
The last several years have seen major progress towards
the goal of translating our growing understanding of the molecular
basis of cancer into drugs with improved therapeutic activity
and selectivity. Tremendous advances have been made but significant
obstacles remain. In this review we assess our experience
in the design and development of signal transduction drugs
for cancer treatment, with a specific focus on small molecule
kinase inhibitors. The druggability of cancer kinome targets
is exemplified by imatinib, gefitinib, erlotinib and many
other emerging agents. We assess the current status of the
design of potent and selective kinase inhibitors, which has
benefited greatly from high throughput screening and structure-based
approaches. A diverse range of kinase inhibitory scaffolds
is now available based on these methods. Multi-parameter optimisation
now focuses as much on pharmacokinetic and metabolic properties
as it does on target potency and selectivity. Development
of a ‘molecular audit trail’ requiring assays
to demonstrate mechanism of action in vitro and in
vivo is essential. Current issues include our relatively
poor ability to predict the level of kinase selectivity in
the intact cell, uncertainties around the most desirable selectivity
profile, and the emergence of drug resistance.
[Back to top]
Nuclear Factor-κB: A Holy Grail in Cancer Prevention
and Therapy
Bharat B. Aggarwal, Gautam Sethi, Asha Nair and Haruyo
Ichikawa
[Full Text Article]
Nuclear factor-κB
(NF-κB)
is a transcription factor that is activated in response to
various inflammatory stimuli such as cytokines, growth factors,
hormones, mitogens, carcinogens, chemotherapeutic agents,
viral products, eukaryotic parasites, endotoxin, fatty acids,
metals, radiation, hypoxia, and psychological, physical, oxidative,
and chemical stresses. In addition, constitutively active
NF-κB
is frequently encountered in a wide variety of tumors, including
breast, ovarian, colon, pancreatic, thyroid, prostate, lung,
head and neck, bladder, and skin cancers; B-cell lymphoma;
Hodgkin’s disease; T-cell lymphoma; adult T-cell leukemia;
acute lymphoblastic leukemia; multiple myeloma; chronic lymphocytic
leukemia; and acute myelogenous leukemia. Furthermore, NF-κB
activation has been shown to regulate the expression of over
400 genes involved in cellular transformation, proliferation,
inflammation, viral replication, antiapoptosis, angiogenesis,
invasion and metastasis, oxidative stress, and osteoclastogenesis.
Therefore, because of the critical role NF-κB
plays in the pathogenesis of cancer, specific inhibitors of
this factor are being sought. Agents that prevent cancer or
inflammation have been found to suppress NF-κB
activation. Although IκBα
kinase is the major kinase, over 30 different protein kinases
have been linked to the activation of NF-κB
by different stimuli. The development of a drug that can specifically
suppress NF-κB
activation requires a full understanding of the mechanism
by which NF-κB
is activated in response to these various stimuli.
[Back to top]
Epithelial Cell Signaling in Helicobacter pylori Infection
Jean E. Crabtree and Michael Naumann
[Full Text Article]
The human microbial pathogen Helicobacter pylori colonises
the stomach of more than half of the world’s population.
The microorganism can induce chronic gastritis, peptic ulceration
and more rarely, gastric adenocarcinoma. Highly virulent H.
pylori strains carry a cag pathogenicity
island (cag PAI), which encodes proteins involved
in a specialised type IV secretion system (T4SS). H. pylori
induces T4SS-dependent and -independent processes by which
H. pylori takes direct command of gastric epithelial
cell signaling. The H. pylori effector protein cytotoxin
associated gene A (CagA), which is translocated via the T4SS
into epithelial cells, contributes to the modulation of cellular
functions. In addition, H. pylori transactivates
the EGFR, a process involving inter-receptor cross talk and
extracellular ADAM metalloproteinase cleavage of membrane
bound EGFR ligands. The multiple signal transduction pathways
activated during H. pylori infection lead to a complex
series of events promoting inappropriate inflammatory responses,
epithelial hyperproliferation, epithelial survival and transformation.
The H. pylori induced epithelial cellular changes,
as well as chemopreventative therapeutic strategies, will
be introduced in this review.
[Back to top]
Signal Transduction Therapy with Rationally Designed
Kinase Inhibitors
György Kéri, László O"rfi,
Dániel Ero"s, Bálint Hegymegi-Barakonyi,
Csaba Szántai-Kis, Zoltán Horváth, Frigyes
Wáczek, Jen o" Marosfalvi, István Szabadkai,
János Pató, Zoltán Greff, Doris Hafenbradl,Henrik
Daub, Gerhard Müller, Bert Klebl and Axel Ullrich
[Full Text Article]
Signal transduction therapy has become one of the most important
areas of drug research. Signaling disorders represent a major
cause for the pathological states and many of the recently
identified validated target molecules of drug research are
signal transduction related macromolecules, mostly kinases.
Rational drug design is aimed to achieve the selective inhibition
of distinct pathologically relevant signaling enzymes or receptors.
In the previous years, the concept of rational drug design
has been expanded for a complex process including pathomechanism-based
target selection, target validation, structural biology, molecular
modeling, structure-activity relationships, pharmacophore-based
compound selection and pharmacological optimization. The two
main branches of the chemical rational drug design are structure-based
design and ligand-based design. Some important examples for
the application of 3D structure-based rational drug design
in the development of clinically relevant kinase inhibitors
are presented. The Nested Chemical Library™ (NCL) technology
is a ligand-based design approach and relies on a knowledge-based
approach, where focused libraries around published leads and
selected cores are used to generate extended pharmacophore
models (Prediction Oriented QSAR). NCL was designed on the
platform of a diverse kinase inhibitor library, consisting
of small molecule heterocycles, which are organized around
108 core structures. Some examples for testing the library
on various targets and Prediction Oriented QSAR models will
also be presented. The core elements of the kinase family-biased
masterkey concept are the so-called privileged structures
that emerge from a sophisticated molecular design and optimization
process that encodes for a target family-wide structural commonality
in ligand binding. The combination of a kinase family-wide
imprinted commonality with additional structural fragments
in the molecular periphery of a once established privileged
structure allows to synthesize highly active and selective
kinase inhibitors. In addition, several kinase inhibitors
in preclinical or clinical development and application of
3D structure based rational drug design in the development
of clinically relevant kinase inhibitors are reviewed.
[Back to top]
Polypeptide and Protein Aggregates with Neurotoxic
Properties in Neuro-degenerative Disorders: Emphasis on β-Amyloid-Induced
Dysfunction of Receptor-Mediated Signal Transduction Pathways
Yann Verdier and Botond Penke
[Full Text Article]
Polypeptides and proteins may undergo misfolding processes
resulting in aggregates: oligomers and fibrils possessing
toxic properties. In most cases a beta-structure will be formed
with high tendency to form suprachemical structures, assemblies.
The aggregation grade might play crucial role in the biological
activities of protein assemblies. Protein aggregates bind
to receptors or receptor complexes of neuronal and glial cells
and activate signal transduction pathways. Beta amyloid may
interact with Wnt receptors as well as increases the intracellular
Ca-ion level in neurons. GSK-3beta activation causes tau-hyperphosphorylation
and collaps of the microtubular system. β-amyloid
triggers also a CD36 dependent signaling cascade and activates
microglia. Other misfolded protein assemblies of alpha-synuclein,
huntingtin and prion proteins similarly interact with receptor
complexes and disturb signal transduction. Rational drug design
may start after understanding these signalisation disturbances.
Novel drugs will prevent receptor interaction with misfolded
protein aggregates.
[Back to top]
Molecular Targeting of Cell Death Signal Transduction
Pathways in Cancer
Istvan Petak, Janet A. Houghton and Laszlo Kopper
[Full Text Article]
Suppression of cell death (most often apoptosis) by survival
signals, or by defects in cell death signal transduction pathways,
is considered one of the obligate hallmarks of malignant transformation.
However, molecular survival strategies to evade cell death
only have relevance in the presence of pro-death signals.
Discovery of the apoptotic properties of oncogenes responsible
for increased tumor cell proliferation (e.g. c-Myc) provided
the most important example for such signals and led to the
concept of synthetic lethal targeting as a strategy of identifying
cancer specific drug target molecules. Besides growth signal
autonomy, other hallmarks of oncogenesis (insensitivity to
anti-growth signals, limitless replicative potential, invasion
and metastasis, angiogenesis and increased genomic instability)
are also challenged by increased susceptibility to various
forms of cell death. Therefore, cancer cells must acquire
survival strategies to suppress these cell death/apoptosis
mechanisms. Novel signal transduction therapies can target
molecules involved in these strategies to trigger tumor specific
cell death.
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