Protein Kinase CK2 and SARS-CoV-2: An Expected Interplay Story

Meza, Camila Paz Quezada; Ruzzene, Maria

doi:10.3390/kinasesphosphatases1020009

Cited by 13 publications

(9 citation statements)

References 73 publications

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“…The polyamine spermine destabilized the oligomeric structure, probably by a competition with CK2β for binding to the basic stretch of CK2α [54,62]. This observation is comparable with the activation of CK2 kinase activity by polyamines [70,71]. Oligomerization of the holoenzyme is necessary for an autophosphorylation of CK2β [8].…”

Section: Genes and Proteinsmentioning

confidence: 60%

Protein Kinase CK2α’, More than a Backup of CK2α

Montenarh,

Götz

2023

Cells

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The serine/threonine protein kinase CK2 is implicated in the regulation of fundamental processes in eukaryotic cells. CK2 consists of two catalytic α or α’ isoforms and two regulatory CK2β subunits. These three proteins exist in a free form, bound to other cellular proteins, as tetrameric holoenzymes composed of CK2α2/β2, CK2αα’/β2, or CK2α’2/β2 as well as in higher molecular forms of the tetramers. The catalytic domains of CK2α and CK2α’ share a 90% identity. As CK2α contains a unique C-terminal sequence. Both proteins function as protein kinases. These properties raised the question of whether both isoforms are just backups of each other or whether they are regulated differently and may then function in an isoform-specific manner. The present review provides observations that the regulation of both CK2α isoforms is partly different concerning the subcellular localization, post-translational modifications, and aggregation. Up to now, there are only a few isoform-specific cellular binding partners. The expression of both CK2α isoforms seems to vary in different cell lines, in tissues, in the cell cycle, and with differentiation. There are different reports about the expression and the functions of the CK2α isoforms in tumor cells and tissues. In many cases, a cell-type-specific expression and function is known, which raises the question about cell-specific regulators of both isoforms. Another future challenge is the identification or design of CK2α’-specific inhibitors.

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Section: Genes and Proteinsmentioning

confidence: 60%

Protein Kinase CK2α’, More than a Backup of CK2α

Montenarh,

Götz

2023

Cells

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“…The naphthyridine scaffold gave rise to the most clinically advanced CK2 inhibitor: CX-4945 (Figure 2). This compound, despite its suboptimal selectivity (Table 2), has advanced into clinical trials for several oncological indications as well as for the treatment of COVID-19 [19,[46][47][48]. Efforts have been made to improve the selectivity of naphthyridinebased CK2 inhibitors.…”

Section: Selected Orthosteric Ck2 Inhibitors and Chemical Probesmentioning

confidence: 99%

CK2 Chemical Probes: Past, Present, and Future

Ong,

Drewry,

Axtman

2023

Kinases and Phosphatases

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Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug candidates and potent and selective CK2 chemical probes to interrogate CK2 function. Here, we review the small molecule inhibitors reported for CK2 and discuss various orthosteric, allosteric, and bivalent inhibitors of CK2. We focus on the pyrazolo[1,5-a]pyrimidines and naphthyridines, two chemotypes that have been extensively explored for chemical probe development. We highlight the uptake and demonstrated utility of the pyrazolo[1,5-a]pyrimidine chemical probe SGC-CK2-1 by the scientific community in cellular studies. Finally, we propose criteria for an ideal in vivo chemical probe for investigating CK2 function in a living organism. While no compound currently meets these metrics, we discuss ongoing and future directions in the development of in vivo chemical probes for CK2.

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“…9,10 This suggests that CK2 plays an important role in various cellular processes and that an aberrant function of this key regulator can ultimately lead to the development of various disease phenotypes. CK2 associated diseases range from cancer 11,12 and neurodegenerative diseases [13][14][15] to viral [16][17][18][19] and parasitic infections 20,21 , making CK2 an attractive potential target for the development of small molecule based therapies (Figure 1). [22][23][24][25] The most frequently used inhibitor in the literature is CX-4945 (Silmitasertib).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting

Greco,

Krämer,

Wahl

et al. 2024

Preprint

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Casein kinase-2 (CK2) are serine/threonine kinases with dual co-factor (ATP and GTP) specificity, that are involved in the regulation of a wide variety of cellular functions. Small molecules targeting CK2 have been described in the literature targeting different binding pockets of the kinase with a focus on type I inhibitors such as the recently published chemical probe SGC-CK2-1. In this study, we investigated whether known allosteric inhibitors binding to a pocket adjacent to helix αD could be combined with ATP mimetic moieties defining a novel class of ATP competitive compounds with a unique binding mode. Linking both binding sites requires a chemical linking moiety that would introduce a 90-degree angle between the ATP mimetic ring system and the αD targeting moiety, which was realized using a sulfonamide. The synthesized inhibitors were highly selective for CK2 with binding constants in the nM range and low micromolar activity. While these inhibitors need to be further improved, the present work provides a structure-based design strategy for highly selective CK2 inhibitors.

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Protein Kinase CK2 and SARS-CoV-2: An Expected Interplay Story

Cited by 13 publications

References 73 publications

Protein Kinase CK2α’, More than a Backup of CK2α

Protein Kinase CK2α’, More than a Backup of CK2α

CK2 Chemical Probes: Past, Present, and Future

Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting

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