Abstract
CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of “non oncogene addiction”. A wide spectrum of cell permeable, fairly specific ATP sitedirected CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their “normal” counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelmans disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.
Keywords: CK2, quinalizarin, non-oncogene addiction, Promiscuity Score, PIM-1, HIPK2, DYRK1A, ERK-8, cancer, apoptosis, Castelman's disease, multiple myeloma
Current Topics in Medicinal Chemistry
Title: ATP Site-Directed Inhibitors of Protein Kinase CK2: An Update
Volume: 11 Issue: 11
Author(s): S. Sarno, E. Papinutto, C. Franchin, J. Bain, M. Elliott, F. Meggio, Z. Kazimierczuk, A. Orzeszko, G. Zanotti, R. Battistutta and L. A. Pinna
Affiliation:
Keywords: CK2, quinalizarin, non-oncogene addiction, Promiscuity Score, PIM-1, HIPK2, DYRK1A, ERK-8, cancer, apoptosis, Castelman's disease, multiple myeloma
Abstract: CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of “non oncogene addiction”. A wide spectrum of cell permeable, fairly specific ATP sitedirected CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their “normal” counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelmans disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.
Export Options
About this article
Cite this article as:
Sarno S., Papinutto E., Franchin C., Bain J., Elliott M., Meggio F., Kazimierczuk Z., Orzeszko A., Zanotti G., Battistutta R. and A. Pinna L., ATP Site-Directed Inhibitors of Protein Kinase CK2: An Update, Current Topics in Medicinal Chemistry 2011; 11 (11) . https://dx.doi.org/10.2174/156802611795589638
DOI https://dx.doi.org/10.2174/156802611795589638 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Valproic Acid As Anti-Cancer Drug
Current Pharmaceutical Design Uric Acid and Hypertension
Current Pharmaceutical Design Immunotherapy of Cancer Based on DC-Tumor Fusion Vaccine
Current Immunology Reviews (Discontinued) circEPSTI1 Acts as a ceRNA to Regulate the Progression of Osteosarcoma
Current Cancer Drug Targets Anti-CD20 Antibody in Primary Sjogren's Syndrome Managemen
Current Pharmaceutical Biotechnology Melittin: A Natural Peptide with Expanded Therapeutic Applications
The Natural Products Journal Melanoma Immunotherapy: Past, Present, and Future
Current Pharmaceutical Design Structural Models of Protein-DNA Complexes Based on Interface Prediction and Docking
Current Protein & Peptide Science Glycerophospholipid Synthesis as a Novel Drug Target Against Cancer
Current Molecular Pharmacology Bruton's Tyrosine Kinase Inhibition in the Treatment of Preclinical Models and Multiple Sclerosis
Current Pharmaceutical Design New N’-Arylidene-2-[(4-Nitrophenyl)Piperazın-1-yl]Acetohydrazide Derivatives: Synthesis and Anticancer Activity Investigation
Letters in Drug Design & Discovery Preclinical Studies of PROTACs in Hematological Malignancies
Cardiovascular & Hematological Disorders-Drug Targets Distamycin A as Stem of DNA Minor Groove Alkylating Agents
Current Topics in Medicinal Chemistry Tumor Vasculature Targeting Through NGR Peptide-Based Drug Delivery Systems
Current Pharmaceutical Biotechnology Targeting Regulatory T Cells for Anticancer Therapy
Mini-Reviews in Medicinal Chemistry Context-dependent Action of Transforming Growth Factor β Family Members on Normal and Cancer Stem Cells
Current Pharmaceutical Design Cannabinoid Type 2 Receptor as a Target for Chronic - Pain
Mini-Reviews in Medicinal Chemistry Administration of Drug and Nutritional Components in Nano-Engineered Form to Increase Delivery Ratio and Reduce Current Inefficient Practice
Recent Patents on Drug Delivery & Formulation Coumarins as Antioxidants
Current Medicinal Chemistry Cyclin Dependent Kinase 1 Inhibitors: A Review of Recent Progress
Current Medicinal Chemistry