Special Issue "An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 November 2016)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Guest Editor
Prof. Dr. Joachim Jose

PharmaCampus Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität, Corrensstr. 48, 48149, Muenster, Germany
Website | E-Mail
Interests: autodisplay; assay development and inhibitor testing; whole cell biocatalysts for synthesis of drugs and building blocks; directed evolution of enzyme inhibitors and biocatalysts; biosensor development and diagnostic tools
Guest Editor
Prof. Dr. Marc Le Borgne

EA 4446 Bioactive Molecules and Medicinal Chemistry, Faculté de Pharmacie—ISPB, Université Lyon 1, Université de Lyon, SFR Santé Lyon-Est CNRS UMS3453—INSERM US7, 69373 Lyon cedex 8, France
Website | E-Mail
Interests: ligand-based drug design; small molecules; heterocycles; glycoconjugates; structure-activity relationships; structural optimization; stability studies; cancer; chemoresistances; infectious diseases
Guest Editor
Prof. Dr. Lorenzo A. Pinna

Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, 35131 Padova, Italy
Website | E-Mail
Interests: protein phosphorylation in signal transduction; structure-function analysis and definition of specificity determinants of protein kinases implicated in cell proliferation and apoptosis. molecules currently in focus are a number of pleiotropic acidophilic Ser/Thr kinases, notably CK2, CK1, and Dyrk
Guest Editor
Prof. Dr. Mathias Montenarh

Medizinische Biochemie und Molekularbiologie, Faculty of Medicine, Saarland University Geb. 44/45, D-66424 Homburg, Germany
Website | E-Mail
Interests: reversible protein phosphorylation; cell signalling; reactive oxygen species; ER stress; apoptosis

Special Issue Information

Dear Colleagues,

The 8th International Conference on Protein Kinase CK2 (www.uks.eu/ck2), organized by Matthias Montenarh and Claudia Götz, will be held at the Faculty of Medicine of Saarland University, in Homburg, Germany, from 6–9 September, 2016.

Protein kinase CK2 is a serine/threonine kinase, which is highly conserved in evolution. Knock-out experiments have shown that this enzyme is absolutely necessary for cell viability. The enzyme is highly expressed in rapidly proliferating cells, which goes along with an elevated enzyme activity. Protein kinase CK2 is involved in a broad range of signaling pathways, regulating proliferation, differentiation, apoptosis, or senescence. Recent advances towards the characterization of the three-dimensional structure of protein kinase CK2 and its subunits will undoubtedly yield important new insights into its regulation, and the functions of CK2. Moreover, with two inhibitors of the enzyme presently in clinical phase II trials, human protein kinase CK2 has appeared as an emerging target for cancer diseases.

Speakers at the conference are cordially invited to contribute original research papers or reviews to this Special Issue of Pharmaceuticals.

Prof. Dr. Joachim Jose
Prof. Dr. Marc Le Borgne
Prof. Dr. Lorenzo A. Pinna
Prof. Dr. Mathias Montenarh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind 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 quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 850 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein kinase
  • cancer disease
  • signal transduction
  • therapeutic target
  • structural biology

Published Papers (19 papers)

View options order results:
result details:
Displaying articles 1-19
Export citation of selected articles as:

Editorial

Jump to: Research, Review

Open AccessEditorial An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2
Pharmaceuticals 2017, 10(2), 33; https://doi.org/10.3390/ph10020033
Received: 20 March 2017 / Revised: 21 March 2017 / Accepted: 21 March 2017 / Published: 23 March 2017
Cited by 1 | PDF Full-text (173 KB) | HTML Full-text | XML Full-text
Abstract
The 8th International Conference on Protein Kinase CK2 took place in Homburg, Germany, from 6 September to 9 September 2016.[...] Full article

Research

Jump to: Editorial, Review

Open AccessArticle Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice
Pharmaceuticals 2017, 10(1), 24; https://doi.org/10.3390/ph10010024
Received: 30 November 2016 / Revised: 1 February 2017 / Accepted: 6 February 2017 / Published: 12 February 2017
Cited by 7 | PDF Full-text (2433 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human [...] Read more.
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. Full article
Figures

Figure 1

Open AccessArticle Inhibition of Protein Kinase CK2 Prevents Adipogenic Differentiation of Mesenchymal Stem Cells Like C3H/10T1/2 Cells
Pharmaceuticals 2017, 10(1), 22; https://doi.org/10.3390/ph10010022
Received: 29 November 2016 / Revised: 20 January 2017 / Accepted: 7 February 2017 / Published: 9 February 2017
Cited by 2 | PDF Full-text (1787 KB) | HTML Full-text | XML Full-text
Abstract
Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. [...] Read more.
Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α’-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. Mesenchymal stem cells (MSCs) are multipotent cells which can be differentiated into adipocytes in vitro. Thus, MSCs and in particular C3H/10T1/2 cells are excellent tools to study a possible role of CK2 in adipogenesis. We found downregulation of the CK2 catalytic subunits as well as a decrease in CK2 kinase activity with progression of differentiation. Inhibition of CK2 using the potent inhibitor CX-4945 impeded differentiation of C3H/10T1/2 cells into adipocytes. The inhibited cells lacked the observed decrease in CK2 expression, but showed a constant expression of all three CK2 subunits. Furthermore, inhibition of CK2 resulted in decreased cell proliferation in the early differentiation phase. Analysis of the main signaling cascade revealed an elevated expression of C/EBPβ and C/EBPδ and reduced expression of the adipogenic master regulators C/EBPα and PPARγ2. Thus, CK2 seems to be implicated in the regulation of different steps early in the adipogenic differentiation of MSC. Full article
Figures

Figure 1

Open AccessArticle In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface
Pharmaceuticals 2017, 10(1), 16; https://doi.org/10.3390/ph10010016
Received: 25 November 2016 / Revised: 16 January 2017 / Accepted: 22 January 2017 / Published: 3 February 2017
Cited by 6 | PDF Full-text (3865 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. [...] Read more.
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way. Full article
Figures

Figure 1

Open AccessArticle Ablation of Protein Kinase CK2β in Skeletal Muscle Fibers Interferes with Their Oxidative Capacity
Pharmaceuticals 2017, 10(1), 13; https://doi.org/10.3390/ph10010013
Received: 3 December 2016 / Revised: 13 January 2017 / Accepted: 14 January 2017 / Published: 19 January 2017
Cited by 3 | PDF Full-text (2044 KB) | HTML Full-text | XML Full-text
Abstract
The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be [...] Read more.
The tetrameric protein kinase CK2 was identified playing a role at neuromuscular junctions by studying CK2β-deficient muscle fibers in mice, and in cultured immortalized C2C12 muscle cells after individual knockdown of CK2α and CK2β subunits. In muscle cells, CK2 activity appeared to be at least required for regular aggregation of nicotinic acetylcholine receptors, which serves as a hallmark for the presence of a postsynaptic apparatus. Here, we set out to determine whether any other feature accompanies CK2β-deficient muscle fibers. Hind limb muscles gastrocnemius, plantaris, and soleus of adult wildtype and CK2β-deficient mice were dissected, cross-sectioned, and stained histochemically by Gomori trichrome and for nicotinamide adenine dinucleotide (NADH) dehydrogenase and succinate dehydrogenase (SDH) enzymatic activities. A reduction of oxidative enzymatic activity was determined for CK2β-deficient muscle fibers in comparison with wildtype controls. Importantly, the CK2β-deficient fibers, muscle fibers that typically exhibit high NADH dehydrogenase and SDH activities, like slow-type fibers, showed a marked reduction in these activities. Altogether, our data indicate additional impairments in the absence of CK2β in skeletal muscle fibers, pointing to an eventual mitochondrial myopathy. Full article
Figures

Figure 1

Open AccessArticle Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3-d]pyrimidine-Based Inhibitor
Pharmaceuticals 2017, 10(1), 9; https://doi.org/10.3390/ph10010009
Received: 1 December 2016 / Revised: 3 January 2017 / Accepted: 5 January 2017 / Published: 11 January 2017
Cited by 7 | PDF Full-text (3288 KB) | HTML Full-text | XML Full-text
Abstract
Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog [...] Read more.
Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations. Full article
Figures

Figure 1

Open AccessArticle Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining
Pharmaceuticals 2017, 10(1), 8; https://doi.org/10.3390/ph10010008
Received: 13 December 2016 / Revised: 3 January 2017 / Accepted: 4 January 2017 / Published: 9 January 2017
Cited by 5 | PDF Full-text (3713 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different [...] Read more.
Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50 value of 1.24 µM. Full article
Figures

Figure 1

Open AccessArticle Identification of a Potent Allosteric Inhibitor of Human Protein Kinase CK2 by Bacterial Surface Display Library Screening
Pharmaceuticals 2017, 10(1), 6; https://doi.org/10.3390/ph10010006
Received: 30 November 2016 / Revised: 24 December 2016 / Accepted: 27 December 2016 / Published: 5 January 2017
Cited by 3 | PDF Full-text (4364 KB) | HTML Full-text | XML Full-text
Abstract
Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to [...] Read more.
Human protein kinase CK2 has emerged as promising target for the treatment of neoplastic diseases. The vast majority of kinase inhibitors known today target the ATP binding site, which is highly conserved among kinases and hence leads to limited selectivity. In order to identify non-ATP competitive inhibitors, a 12-mer peptide library of 6 × 105 variants was displayed on the surface of E. coli by autodisplay. Screening of this peptide library on variants with affinity to CK2 was performed by fluorophore-conjugated CK2 and subsequent flow cytometry. Single cell sorting of CK2-bound E. coli yielded new peptide variants, which were tested on inhibition of CK2 by a CE-based assay. Peptide B2 (DCRGLIVMIKLH) was the most potent inhibitor of both, CK2 holoenzyme and the catalytic CK2α subunit (IC50 = 0.8 µM). Using different ATP concentrations and different substrate concentrations for IC50 determination, B2 was shown to be neither ATP- nor substrate competitive. By microscale thermophoresis (MST) the KD value of B2 with CK2α was determined to be 2.16 µM, whereas no binding of B2 to CK2β-subunit was detectable. To our surprise, besides inhibition of enzymatic activity, B2 also disturbed the interaction of CK2α with CK2β at higher concentrations (≥25 µM). Full article
Figures

Graphical abstract

Open AccessArticle D11-Mediated Inhibition of Protein Kinase CK2 Impairs HIF-1α-Mediated Signaling in Human Glioblastoma Cells
Pharmaceuticals 2017, 10(1), 5; https://doi.org/10.3390/ph10010005
Received: 1 November 2016 / Revised: 13 December 2016 / Accepted: 22 December 2016 / Published: 1 January 2017
Cited by 2 | PDF Full-text (1319 KB) | HTML Full-text | XML Full-text
Abstract
Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer [...] Read more.
Compelling evidence indicates that protein kinase CK2 plays an important role in many steps of cancer initiation and progression, therefore, the development of effective and cell-permeable inhibitors targeting this kinase has become an important objective for the treatment of a variety of cancer types including glioblastoma. We have recently identified 1,3-dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl]dibenzo(b,d)furan-2,7-diol (D11) as a potent and selective inhibitor of protein kinase CK2. In this study, we have further characterized this compound and demonstrated that it suppresses CK2 kinase activity by mixed type inhibition (KI 7.7 nM, KI′ 42 nM). Incubation of glioblastoma cells with D11 induces cell death and upon hypoxia the compound leads to HIF-1α destabilization. The analysis of differential mRNA expression related to human hypoxia signaling pathway revealed that D11-mediated inhibition of CK2 caused strong down-regulation of genes associated with the hypoxia response including ANGPTL4, CA9, IGFBP3, MMP9, SLC2A1 and VEGFA. Taken together, the results reported here support the notion that including D11 in future treatment regimens might turn out to be a promising strategy to target tumor hypoxia to overcome resistance to radio- and chemotherapy. Full article
Figures

Figure 1

Open AccessArticle The Phosphorylation of PDX-1 by Protein Kinase CK2 Is Crucial for Its Stability
Pharmaceuticals 2017, 10(1), 2; https://doi.org/10.3390/ph10010002
Received: 24 November 2016 / Revised: 20 December 2016 / Accepted: 23 December 2016 / Published: 28 December 2016
Cited by 3 | PDF Full-text (2781 KB) | HTML Full-text | XML Full-text
Abstract
The homeodomain protein PDX-1 is a critical regulator of pancreatic development and insulin production in pancreatic β-cells. We have recently shown that PDX-1 is a substrate of protein kinase CK2; a multifunctional protein kinase which is implicated in the regulation of various cellular [...] Read more.
The homeodomain protein PDX-1 is a critical regulator of pancreatic development and insulin production in pancreatic β-cells. We have recently shown that PDX-1 is a substrate of protein kinase CK2; a multifunctional protein kinase which is implicated in the regulation of various cellular aspects, such as differentiation, proliferation, and survival. The CK2 phosphorylation site of PDX-1 is located within the binding region of the E3 ubiquitin ligase adaptor protein PCIF1. To study the interaction between PDX-1 and PCIF1 we used immunofluorescence analysis, co-immunoprecipitation, GST-pull-down studies, and proximity ligation assay (PLA). For the analysis of the stability of PDX-1 we performed a cycloheximide chase. We used PDX-1 in its wild-type form as well as phosphomutants of the CK2 phosphorylation site. In pancreatic β-cells PDX-1 binds to PCIF1. The phosphorylation of PDX-1 by CK2 increases the ratio of PCIF1 bound to PDX-1. The stability of PDX-1 is extended in the absence of CK2 phosphorylation. Our results identified protein kinase CK2 as new important modulator of the stability of PDX-1. Full article
Figures

Figure 1

Review

Jump to: Editorial, Research

Open AccessReview Protein Kinase CK2: Intricate Relationships within Regulatory Cellular Networks
Pharmaceuticals 2017, 10(1), 27; https://doi.org/10.3390/ph10010027
Received: 14 January 2017 / Revised: 25 February 2017 / Accepted: 2 March 2017 / Published: 5 March 2017
Cited by 7 | PDF Full-text (4693 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered [...] Read more.
Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory participant in intricately controlled cellular processes. To resolve this apparent paradox, we have performed a systematic analysis of the published literature using text mining as well as mining of proteomic databases together with computational assembly of networks that involve CK2. These analyses reinforce the notion that CK2 is involved in a broad variety of biological processes and also reveal an extensive interplay between CK2 phosphorylation and other post-translational modifications. The interplay between CK2 and other post-translational modifications suggests that CK2 does have intricate roles in orchestrating cellular events. In this respect, phosphorylation of specific substrates by CK2 could be regulated by other post-translational modifications and CK2 could also have roles in modulating other post-translational modifications. Collectively, these observations suggest that the actions of CK2 are precisely coordinated with other constituents of regulatory cellular networks. Full article
Figures

Figure 1

Open AccessReview CK2 Molecular Targeting—Tumor Cell-Specific Delivery of RNAi in Various Models of Cancer
Pharmaceuticals 2017, 10(1), 25; https://doi.org/10.3390/ph10010025
Received: 7 December 2016 / Revised: 6 February 2017 / Accepted: 14 February 2017 / Published: 21 February 2017
Cited by 3 | PDF Full-text (1993 KB) | HTML Full-text | XML Full-text
Abstract
Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; [...] Read more.
Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells. The latter is particularly important since CK2 is a ubiquitous signal that is essential for survival. To achieve these goals, we have developed a nanocapsule that has the properties of delivering an anti-CK2 RNAi therapeutic cargo, in a protected manner, specifically to cancer cells. Tenfibgen (TBG) is used as the ligand to target tenascin-C receptors, which are elevated in cancer cells. This strategy is effective for inhibiting growth and inducing death in several types of xenograft tumors, and the nanocapsule elicits no safety concerns in animals. Further investigation of this therapeutic approach for its translation is warranted. Full article
Figures

Figure 1

Open AccessReview The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design
Pharmaceuticals 2017, 10(1), 26; https://doi.org/10.3390/ph10010026
Received: 15 December 2016 / Accepted: 14 February 2017 / Published: 20 February 2017
Cited by 10 | PDF Full-text (3586 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown [...] Read more.
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by “trial and error testing”. In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising. Full article
Figures

Figure 1

Open AccessReview The Link between Protein Kinase CK2 and Atypical Kinase Rio1
Pharmaceuticals 2017, 10(1), 21; https://doi.org/10.3390/ph10010021
Received: 30 November 2016 / Revised: 27 January 2017 / Accepted: 4 February 2017 / Published: 7 February 2017
Cited by 1 | PDF Full-text (4276 KB) | HTML Full-text | XML Full-text
Abstract
The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the [...] Read more.
The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors. Full article
Figures

Figure 1

Open AccessReview CK2 in Cancer: Cellular and Biochemical Mechanisms and Potential Therapeutic Target
Pharmaceuticals 2017, 10(1), 18; https://doi.org/10.3390/ph10010018
Received: 2 December 2016 / Revised: 23 January 2017 / Accepted: 23 January 2017 / Published: 28 January 2017
Cited by 22 | PDF Full-text (493 KB) | HTML Full-text | XML Full-text
Abstract
CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer [...] Read more.
CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer including inhibition of apoptosis, modulation of signaling pathways, DNA damage response, and cell cycle regulation. A number of CK2 inhibitors are now available and have been shown to have activity against various cancers in vitro and in pre-clinical models. Some of these inhibitors are now undergoing exploration in clinical trials as well. In this review, we will examine some of the major cancers in which CK2 inhibition has promise based on in vitro and pre-clinical studies, the proposed cellular and signaling mechanisms of anti-cancer activity by CK2 inhibitors, and the current or recent clinical trials using CK2 inhibitors. Full article
Figures

Figure 1

Open AccessReview Exploring the CK2 Paradox: Restless, Dangerous, Dispensable
Pharmaceuticals 2017, 10(1), 11; https://doi.org/10.3390/ph10010011
Received: 28 November 2016 / Revised: 12 January 2017 / Accepted: 16 January 2017 / Published: 20 January 2017
Cited by 11 | PDF Full-text (1090 KB) | HTML Full-text | XML Full-text
Abstract
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but [...] Read more.
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its “lateral” implication in a variety of signaling pathways is now soundly documented. At variance with many “onco-kinases”, CK2 is constitutively active, and no oncogenic CK2 mutant is known; still high CK2 activity correlates to neoplasia. Its pleiotropy and essential role may cast doubts on the actual “druggability” of CK2; however, a CK2 inhibitor is now in Phase II clinical trials for the treatment of cancer, and cell clones viable in the absence of CK2 are providing information about the mechanism by which cancer becomes addicted to high CK2 levels. A phosphoproteomics analysis of these CK2 null cells suggests that CK2 pleiotropy may be less pronounced than expected and supports the idea that the phosphoproteome generated by this kinase is flexible and not rigidly pre-determined. Full article
Figures

Figure 1

Open AccessReview CK2—An Emerging Target for Neurological and Psychiatric Disorders
Pharmaceuticals 2017, 10(1), 7; https://doi.org/10.3390/ph10010007
Received: 30 November 2016 / Revised: 20 December 2016 / Accepted: 30 December 2016 / Published: 5 January 2017
Cited by 6 | PDF Full-text (643 KB) | HTML Full-text | XML Full-text
Abstract
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the [...] Read more.
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders. Full article
Figures

Figure 1

Open AccessReview Drosophila Protein Kinase CK2: Genetics, Regulatory Complexity and Emerging Roles during Development
Pharmaceuticals 2017, 10(1), 4; https://doi.org/10.3390/ph10010004
Received: 29 November 2016 / Revised: 12 December 2016 / Accepted: 19 December 2016 / Published: 29 December 2016
Cited by 2 | PDF Full-text (22421 KB) | HTML Full-text | XML Full-text
Abstract
CK2 is a Ser/Thr protein kinase that is highly conserved amongst all eukaryotes. It is a well-known oncogenic kinase that regulates vital cell autonomous functions and animal development. Genetic studies in the fruit fly Drosophila are providing unique insights into the roles of [...] Read more.
CK2 is a Ser/Thr protein kinase that is highly conserved amongst all eukaryotes. It is a well-known oncogenic kinase that regulates vital cell autonomous functions and animal development. Genetic studies in the fruit fly Drosophila are providing unique insights into the roles of CK2 in cell signaling, embryogenesis, organogenesis, neurogenesis, and the circadian clock, and are revealing hitherto unknown complexities in CK2 functions and regulation. Here, we review Drosophila CK2 with respect to its structure, subunit diversity, potential mechanisms of regulation, developmental abnormalities linked to mutations in the gene encoding CK2 subunits, and emerging roles in multiple aspects of eye development. We examine the Drosophila CK2 “interaction map” and the eye-specific “transcriptome” databases, which raise the prospect that this protein kinase has many additional targets in the developing eye. We discuss the possibility that CK2 functions during early retinal neurogenesis in Drosophila and mammals bear greater similarity than has been recognized, and that this conservation may extend to other developmental programs. Together, these studies underscore the immense power of the Drosophila model organism to provide new insights and avenues to further investigate developmentally relevant targets of this protein kinase. Full article
Figures

Figure 1

Open AccessReview The New Role for an Old Kinase: Protein Kinase CK2 Regulates Metal Ion Transport
Pharmaceuticals 2016, 9(4), 80; https://doi.org/10.3390/ph9040080
Received: 18 November 2016 / Revised: 13 December 2016 / Accepted: 16 December 2016 / Published: 21 December 2016
Cited by 3 | PDF Full-text (606 KB) | HTML Full-text | XML Full-text
Abstract
The pleiotropic serine/threonine protein kinase CK2 was the first kinase discovered. It is renowned for its role in cell proliferation and anti-apoptosis. The complexity of this kinase is well reflected by the findings of past decades in terms of its heterotetrameric structure, subcellular [...] Read more.
The pleiotropic serine/threonine protein kinase CK2 was the first kinase discovered. It is renowned for its role in cell proliferation and anti-apoptosis. The complexity of this kinase is well reflected by the findings of past decades in terms of its heterotetrameric structure, subcellular location, constitutive activity and the extensive catalogue of substrates. With the advent of non-biased high-throughput functional genomics such as genome-wide deletion mutant screening, novel aspects of CK2 functionality have been revealed. Our recent discoveries using the model organism Saccharomyces cerevisiae and mammalian cells demonstrate that CK2 regulates metal toxicity. Extensive literature search reveals that there are few but elegant works on the role of CK2 in regulating the sodium and zinc channels. As both CK2 and metal ions are key players in cell biology and oncogenesis, understanding the details of CK2’s regulation of metal ion homeostasis has a direct bearing on cancer research. In this review, we aim to garner the recent data and gain insights into the role of CK2 in metal ion transport. Full article
Figures

Figure 1

Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top