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  • br Introduction br Conclusion br Acknowledgments and Funding

    2021-04-30


    Introduction
    Conclusion
    Acknowledgments and Funding
    Introduction Reversible protein phosphorylation is an important post-translational modification of proteins regulating many processes in the cell. Approximately one third of the cellular proteome is phosphorylated, and several sites are often modified (Mann et al., 2002). Phosphorylation of proteins on hydroxyl side-chains of serine, threonine and tyrosine is recognized as a key mode of signal transduction and amplification in eukaryotic cells (Ahn and Resing, 2001, Hunter, 2007, Yang, 2005). The Human Genome Project revealed that approximately 20% of human genes code for signal transduction-related proteins including over 520 known protein kinases and 130 protein phosphatases (Yang, 2005). Aberrant expression and/or activation of many members of this group of proteins results in perturbation of signaling (Blume-Jensen and Hunter, 2001, Avendaño and Menèndez, 2015) and have been observed in various cancers and other proliferative diseases (Avendaño and Menèndez, 2015, Vogelstein et al., 2014). Protein kinase CK2 is a ubiquitous, pleiotropic and constitutively active protein kinase, localized in both cytosolic and nuclear compartments of mammalian cell, where it phosphorylates hundreds of proteins at residues mainly located within negatively charged amino NPS-2143 sequences (Meggio and Pinna, 2003, Salvi et al., 2009). The enzyme is traditionally classified as Ser/Thr protein kinase, however, examples of Tyr phosphorylation have also been documented (Marin et al., 1999, Vilk et al., 2008). CK2 has a tetrameric structure composed of two catalytic (α and/or α′) and two regulatory subunits (β). The catalytic subunits α/α′ are active even in the absence of the β subunits, whose major role is the stabilization of the holoenzyme and regulation of substrate selectivity (Bibby and Litchfield, 2005). It has many cellular targets and forms different signaling complexes which reflect the multifunctional nature of this enzyme. There are some peculiar properties associated with protein kinase CK2, which are not found in any other protein phosphotransferase: (1) the enzyme is constitutively active, (2) it can use ATP as well as GTP, and (3) it is found elevated in most investigated rapidly proliferating tissues and tumors (Ahmad et al., 2007, Duncan and Litchfield, 2008, Kim et al., 2007, Litchfield, 2003, Ruzzene and Pinna, 2010). It is believed that CK2 promote tumorigenesis, because its protein content and/or activity are enhanced in many human cancers and rapidly proliferating tissues (Ahmad et al., 2007, Duncan and Litchfield, 2008, Kim et al., 2007, Ruzzene and Pinna, 2010, Trembley et al., 2009). Moreover, CK2 may play an important role in other human disorders due to Alzheimer's disease, ischemia, chronic alcohol exposure, or HIV infection (Blanquet, 2000, Caples et al., 2006). Many reports indicate that deregulated CK2 activity is associated with suppression of apoptosis, and inhibition of CK2 strongly enhances sensitivity of cancer cells to programmed cell death (Ahmad et al., 2007, Ahmad et al., 2008, Duncan and Litchfield, 2008, Götz et al., 2012, Hessenauer et al., 2011, Litchfield, 2003, Yde et al., 2007). Therefore, regulating CK2 activity may be a promising therapeutic intervention for cancer (Cozza et al., 2010, Duncan and Litchfield, 2008, Seeber et al., 2005). In the last three decades numerous inhibitors addressed to the target CK2 were developed. Several potent and relatively specific inhibitors of protein kinase CK2 belong to the classes of tetrabromobenzimidazole/triazole derivatives, condensed polyphenolic compounds, and indoloquinazolines. The structural basis for their selectivity is provided by a hydrophobic pocket adjacent to the ATP/GTP binding site, which in CK2 is smaller than in the majority of other protein kinases (Cozza et al., 2010, Sarno et al., 2005). One of them, the benzonaphthyridine derivative CX-4945, has shown impressive activity in cell culture studies and has reached advanced clinical trials for the treatment of cancer (Pierre et al., 2011).