Special Issue "Protein Kinase Inhibitors"

Guest Editor
Prof. Dr. Lee M. Graves
Department of Pharmacology, University of NC at Chapel Hill, Chapel Hill, NC, Room 4111, Genetic Medicine Building, CB# 7365120 Mason Farm Road, Chapel Hill, NC, 27599-7365, USA
E-Mail:

Submission

All manuscripts should be submitted to pharmaceuticals@mdpi.org with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access monthly journal published by MDPI.

• p38 MAP kinase
• Erk
• Jnk
• Raf
• BCR-Abl,p70 S6 kinase
• mTor
• Pyk2

Manuscript ID: Pharmaceuticals-pki-20091007-Malemud-us
Type of Paper: Review
Title: Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway
Author: Charles J. Malemud
Affiliation: Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA; E-Mail: cjm4@cwru.edu
Abstract: A skewed repertoire of pro-inflammatory cytokines is a hallmark of autoimmune-mediated inflammation, synovial tissue activation and arthritis severity. Several of these pro-inflammatory cytokines, including, IL-6, IL-7, IL-17 and IL-12/IL-23 activate the Jak/STAT signaling pathway. Recent evidence showed that phosphorylated STAT proteins perpetuate autoimmune-mediated inflammatory responses in multiple organ systems. Additionally, evidence has accumulated showing considerable ‘cross-talk’ between activation of JAK/STAT and activation of the SAP/MAPK and PI3K/Akt pathways. Several JAK/STAT small molecule inhibitors which were shown to block pro-inflammatory cytokine-induced inflammation and arthritis severity in well-validated animal models have already made their way into rheumatoid arthritis (RA) clinical trials.

Manuscript ID: Pharmaceuticals-pki-20091013-it-Ribatti
Type of Paper: Review
Title: Protein-Tyrosine Kinase Inhibitors as Antiangiogenic Molecules in the Treatment of Haematological Malignancies
Author: Domenico Ribatti
Affiliation: Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy; E-Mail: ribatti@anatomia.uniba.it
Abstract: Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but rather they are selective against a limited numer of tyrosine kinases. The success of imatinib-mesylate (Gleevec) for the treatment of patients with chronic myeloid leukemia has opened a intensive search for new small molecular compounds able to target other protein tyrosine kinases involved in the malignant transformation.
This review article is focused on the use of tyrosine kinase inhibitors as antiangiogenic molecules in the treatment of haematological malignancies.

Type of Paper: Review
Title: Protein and Lipid Kinase Inhibitors as Treatment Modalities: Potential and Limitation
Author: Doriano Fabbro
Affiliation: Center for Proteomic Chemistry, Head of Kinase Biology, Expertise Platform Kinases, WSJ-152.1.72.1, Fabrikstrasse 16, CH-4056 Basel, Switzerland; E-Mail: doriano.fabbro@novartis.com
Abstract: Protein and lipid kinases fulfill essential roles in many signaling pathways that regulate normal cell functions. Deregulation of these kinase activities lead to a variety of pathologies ranging from cancer, inflammatory diseases, diabetes, infectious diseases, cardiovascular disorders, cell growth and survival. 518 protein kinases and about 20 lipid modifying kinases are encoded by the human genome and a much larger proportion of additional kinases are present in parasites, bacterial, fungal and viral genomes that are susceptible to exploitation as drug targets. Since many human diseases result from over-activation of protein and lipid kinases due to mutations and/or over-expression, these enzyme class represent an important target for the pharmaceutical industry. Approximately one third of all protein targets under investigation in the pharmaceutical industry are protein and lipid kinases, The kinase inhibitors that have been launched, thus far, are mainly in oncology indications and are directed against an handful of protein and lipid kinases. With one exception, all of these registered kinase inhibitors are directed towards the ATP-site and display different selectivities, potencies and pharmacokinetic properties. At present about 150 kinase-targeted drugs are in clinical development and many more in various stages of pre-clinical development. Kinase inhibitor drugs which are in clinical trials, target all stages of signal transduction from the receptor protein tyrosine kinases that initiate intracellular signaling, through second-messenger dependent lipid and protein kinases and protein kinases that regulate the cell cycle. This review will provide an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors and novel avenues for the generation of second generation kinase inhibitors to treat cancers and other indications.

Title: Opportunities to Target Specific Smooth Muscle Contractile Abnormalities with Protein Kinase Inhibitors
Authors: Annegret Ulke-Lemee and Justin A. MacDonald
Affiliation: Smooth Muscle Research Group & Libin Cardiovascular Institute of Alberta, Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, T2N 4Z6, Canada; E-Mail: jmacdo@ucalgary.ca (J.A.M.D.)
Abstract: Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine); therefore, the coordinated regulation of contraction via protein kinases is a key property of smooth muscle, which when functioning normally, contributes to general health and wellness, but when dysfunctional is associated with mobidity and mortality. Rho-associated protein kinase (ROCK) is central to actomyosin-mediated contractile force generation in the vasculature, playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence is also supportive of an important role for ROCK in the increased vasoconstriction, remodeling and peripheral resistance observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. For example, Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications might also benefit from ROCK inhibition. Notwithstanding the importance of ROCK in smooth muscle contraction, a variety of other protein kinases are known to play similar roles in regulating contractile force. The zipper-interacting protein kinase (ZIPK) and integrin-linked kinase (ILK) are two well-described regulators of contraction. The relative contribution of each kinase to contraction depends on the muscle bed as well as hormonal and neuronal stimulation. Unfortunately, specific inhibitors for ZIPK and ILK are not available, but the success of Fasudil suggests that inhibitors for these other kinases may have valuable clinical applications. Notably, the directed inhibition of ZIPK with a pseudosubstrate molecule shows unexpected effects on the contractility of gastrointestinal smooth muscle.