BSP :: Current Signal Transduction Therapy Home Page

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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.