Special Issue "Protein Kinase Inhibitors"

Guest Editor
Prof. Dr. Lee M. Graves
Department of Pharmacology, University of NC at Chapel Hill, Genetic Medicine Building, Room 4111, CB# 7365120 Mason Farm Road, Chapel Hill, NC, 27599-7365, USA
Website: http://www.med.unc.edu/pharm/people/primaryfaculty/lee-m-graves-1/lee-m-graves
E-Mail: lmg@med.unc.edu
Interests: protein phosphorylation and protein kinase-mediated signaling pathways; application of proteomics; protein kinase inhibitors as therapeutics; regulation of metabolic enzymes by phosphorylation and interacting proteins

Submission

All manuscripts should be submitted to pharmaceuticals@mdpi.com 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
• Protein Kinase CK2

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.

Type of Paper: Review
Title: Raf Kinase Inhibitory Protein (RKIP): a Regulator of Cellular Kinase Signaling
Author: MR Rosner 
Affiliation: University of Chicago, 5848 South University Avenue, Chicago, IL 60637, USA; E-Mail: mrosner@uchicago.edu
Abstract: RKIP functions within the cell as an inhibitor of cellular kinases that mediate MAP kinase, GPCR and NFkB signaling. We will describe structure/ function studies elucidating the mechanism by which RKIP responds to kinases such as ERK and PKA and uses this information to regulate the activity of key cellular kinases such as Raf and GRK2. RKIP has also been shown to function as a metastasis suppressor, and we will describe downstream metastasis targets of RKIP related to extracellular matrix, chromatin remodeling and redox potential. Finally, we will discuss RKIP-related prognostic gene signatures for predicting breast cancer patient survival.

Title: cGMP-dependent Protein Kinase Inhibitors in Health and Disease
Authors: Jens Schlossmann, Johannes Hüttner and Stefanie Wolfertstetter
Affiliation: Pharmakologie und Toxikologie, Universität Regensburg, Universitätsstr. 31, D-93040 Regensburg, Germany; E-Mail: jens.schlossmann@chemie.uni-regensburg.de
Abstract: cGMP-dependent protein kinases (cGK) exhibit diverse physiological functions in the mammalian system e.g. in vascular and gastrointestinal smooth muscles, in platelets, in kidney, in bone growth, nociception and in the central nervous system. Furthermore, cGK were found in insects and in the malaria parasite Plasmodium falciparum. Two different genes of cGK exist a) the cGKI gene which is expressed as cytosolic cGKIα or cGKIβ isoform, and b) the cGKII which expresses the membrane associated cGKII protein. The enzyme kinetics, the localization and the substrates of these cGK enzymes differ utilizing different physiological functions. Various inhibitors of cGK were developed directed against diverse functional regions of the kinase. These inhibitors of cGK have been used to analyse the specific functions of these enzymes. The review article will summarize these different inhibitors regarding their specificity and their present applications in vitro and in vivo. Furthermore, it will be discussed that the distinct inhibition of the cGK enzymes could be a used as a valuable pharmacological target e.g. in the treatment of cardiovascular diseases, diarrhea, pain and malaria.

Type of Paper: Article
Title: Improved CK2 Inhibitors: New Functionalization and Corresponding SAR Analysis of Indeno[1,2-b]indole Derivatives
Authors: Faten Al Chab¹, Laurent Ettouati¹, Zouhair Bouaziz¹, Andre Bollake², Joachim Jose², Marc Le Borgne¹
Affiliations: ¹ Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 avenue Rockefeller, F-69373, Lyon Cedex 8, France; E-Mail: MARC.LE-BORGNE@adm.univ-lyon1.fr
² Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Hittorfstraße 58-62, 48149 Münster, Germany
Abstract: Protein kinase CK2 is an ubiquitous serine/threonine kinase found in all eukaryotic cells. Known since 1954, CK2 is a newly validated therapeutic target (e.g. breast carcinoma, prostate carcinoma, leukemia), ideally suited for drug design, and has become for next decades a major target for inhibition. Actually numerous ATP-competitive inhibitors have been identified, which consist of small and planar heterocyclic scaffolds, able to fit into the nucleotide-binding pocket of CK2α and displace the ATP. Among these inhibitors, there are (i) polyhalogenated benzimidazoles and related derivatives, (ii) flavonoids, (iii) anthraquinones, (iv) coumarins, (v) indolo-quinazolines, (vi) pyrazolo-triazines and (vii) carboxyl acid derivatives (e.g. CX-4945). Recently, the indeno[1,2-b]indole series (through the system 6-5-5-6, a combination of 6-membered and 5-membered rings) has revealed great interest as potent and selective ATP-competitive inhibitors of CK2. Structure-Activity Relationship (SAR) studies were ongoing to evaluate the influence of the nature and the position of substituents on the four rings A-D. The first modifications on the C-ring showed that introduction of a non-bulky group (e.g. ethyl, isopropyl) had a favorable inhibitory effect on human CK2. So we continued to explore further structural modifications on the D-ring of the indeno[1,2-b]indole template and this article will present our very last results.