Chemical probes targeting the kinase CK2: a journey outside the catalytic box

Iegre, Jessica; Atkinson, Eleanor L; Brear, P.; Cooper, Bethany M; Hyvönen, Marko; Spring, David R.

doi:10.1039/d1ob00257k

Cited by 25 publications

(37 citation statements)

References 104 publications

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“…In cells, CK2α and CK2α' were identified as bona fide targets of TBB (4,5,6,7-tetrabromo-1H-benzotriazole), TBBz (4,5,6,7-tetrabromo-1H-benzimidazole), and DMAT (2-dimethylamino-4,5,6,7-1H-tetrabromobenzimidazole). The binding site for CK2 inhibitors in this hydrophobic pocket is located at the interface with CK2β [50,51]. Lowering the hyperactivity of CK2 by chemical or molecular methods induces apoptosis in cells and has a significant effect on the inhibition of tumorigenesis [52,53].…”

Section: Ck2 Structure and Functionmentioning

confidence: 99%

“…CDC34 and topoisomerase II are involved in functioning of the cell cycle in glioma cells. CK2 was shown to phosphorylate these cell cycle regulators [51,64]. Several proteins controlled by CK2 have been established to be involved in the maintenance of glioma stem cells, including Wnt/β-catenin, NANOG, OCT4, OLIG2, SHH, and Notch.…”

Section: Ck2 Structure and Functionmentioning

confidence: 99%

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Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

Pucko

Ostrowski

2022

Pharmaceutics

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In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted.

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Section: Ck2 Structure and Functionmentioning

confidence: 99%

Section: Ck2 Structure and Functionmentioning

confidence: 99%

Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms

Pucko

Ostrowski

2022

Pharmaceutics

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“…1 It has a heterotetrameric quaternary structure, consisting of two catalytic subunits (α or α') and two regulatory subunits (β). 2 The α/α' subunits carry out the phosphorylation of target proteins and peptide substrates, whereas the β subunits confer stability to the enzyme, control substrate specificity, and govern cellular localisation of the holoenzyme complex. 3 In particular, CK2β enhances the catalytic activity of CK2α, as well as increasing its thermostability.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15] One such alternative method is via the inhibition of the protein-protein interaction (PPI) between the α and β subunits of CK2; the PPI interface is not as well conserved among other kinases as the ATP active site hence its inhibition is considered a more specific approach. 2 Preventing the formation of the CK2 holoenzyme would induce apoptosis by adjusting the substrate specificity and cellular location of the subunits, thus altering the intracellular environment. 16 Peptides are good PPI modulators as their flexibility and size allows them to adapt to the large and shallow surfaces involved.…”

Section: Introductionmentioning

confidence: 99%

Development of small cyclic peptides targeting the CK2α/β interface

Atkinson

Iegre

D’Amore

et al. 2022

Preprint

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CK2 is a ubiquitous protein kinase, with key roles in the regulation of cell growth and proliferation. In particular, CK2 acts as an anti-apoptotic protein and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is to inhibit the formation of the holoenzyme complex. This is possible, with the most notable example being CAM7117. However, CAM7117 contains unnatural amino acids, residues not directly involved in the binding to CK2, and its size limits further optimisations. In this work, an iterative cycle of enzymatic assays, X-ray crystallography, molecular modelling and cellular assays were used to develop a functionalisable chemical probe for the CK2α/β PPI. The lead peptide, P8C9, successfully binds to CK2α at the protein-protein interaction site, is easily synthesisable and functionalisable, highly stable in serum and small enough to accommodate further optimisation. Furthermore, its cell-permeable analogues, TAT-P8C9 and R3-P8C9, successfully inhibit cell proliferation. TAT-P8C9 and R3-P8C9 can serve as true chemical probes to further understand the intracellular pathways involving CK2, as well as aiding the development of novel CK2 PPI inhibitors for therapeutic use.

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“… 1 It has a heterotetrameric quaternary structure, consisting of two catalytic subunits (α or α′) and two regulatory subunits (β). 2 The α/α′ subunits carry out the phosphorylation of target proteins and peptide substrates, whereas the β subunits confer stability to the enzyme, control substrate specificity, and govern cellular localisation of the holoenzyme complex. 3 In particular, CK2β enhances the catalytic activity of CK2α, as well as increasing its thermostability.…”

mentioning

confidence: 99%