A subnanomolar fluorescent probe for protein kinase CK2 interaction studies

Enkvist, Erki; Viht, Kaido; Bischoff, N.; Vahter, Jürgen; Saaver, Siiri; Raidaru, Gerda; Issinger, Olaf‐Georg; Niefind, Karsten; Uri, Asko

doi:10.1039/c2ob26022k

Cited by 35 publications

(45 citation statements)

References 40 publications

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“…Second, it possesses remarkable affinity toward CK2, and its cellular activity hasb een demonstrated. First, the oligo-aspartate moiety present in previously reported compounds [18,19] was replaced with the corresponding carboxylate-rich peptoid chain comprising N-carboxymethylglycine (iminodiacetic acid, Ida) residues. ATBi se xpected to give two essential polar interactions with the ATPp ocket of CK2.…”

Section: Resultsmentioning

confidence: 99%

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A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

et al. 2017

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Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a K value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC =0.3 μm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development.

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Section: Resultsmentioning

confidence: 99%

“…[17][18][19][20] Both good cellular accumulation and appropriate intracellular compartmentalization are criticalf actorsf or as uccessful PK-inhibitor-based drug. CX-4945, the only ATP-competitive CK2 inhibitor that has reached clinicalt rials, is the mosts uccessful example.…”

Section: Introductionmentioning

confidence: 99%

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

et al. 2017

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“…The crystal structure of CK2 (Protein Data Bank code 4FBX) was used to determine the best docking position for rifampin at the binding site (27). The structure of rifampin was obtained from another Protein Data Bank structure (entry 2HW2) (28).…”

Section: Methodsmentioning

confidence: 99%

Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression

Kim¹,

Hasanuzzaman

Cho

et al. 2015

Journal of Biological Chemistry

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Background: Rifampin is a representative inducer of P-gp, and the only known mechanism is binding between rifampin and PXR. Results: Rifampin directly activates CK2, which phosphorylates Hsp90␤. Consequently, PXR increases, and P-gp expression is induced. Conclusion: A mechanism for inducing P-gp expression by rifampin exposure is newly identified. Significance: A strategy for overcoming P-gp-derived drug resistance is suggested.

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“…[33,34,[36][37][38][39]). A comparison of the IC 50 values within this group showed that only CK2a and CK2a 0 exhibit values below 10 nM.…”

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confidence: 97%

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

Guerra

Hochscherf²,

Jensen³

et al. 2015

Mol Cell Biochem

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The anti-apoptotic protein kinase CK2 increasingly becomes an attractive target in cancer research with great therapeutic potential. Here, we have performed an in vitro screening of the Diversity Set III of the DTP program from the NCI/NIH, comprising 1600 compounds. We have identified 1,3-Dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl] dibenzo(b,d) furan-2,7-diol (referred to as D11) to be a potent and selective inhibitor of protein kinase CK2. The D11 compound was tested against 354 eukaryotic protein kinases. By setting the threshold for inhibition to <2% remaining kinase activity, only DYRK1B, IRAK1 and PIM3 were inhibited to an extent as the tetrameric CK2 holoenzyme and its catalytic subunits α and α'. The IC50 values for the CK2α and CK2α' were on average 1-2 nM in comparison to the DYRK1B, IRAK1 and PIM3 kinases, which ranged from 18 to 49 nM. Cell permeability and efficacy of D11 were tested with cells in culture. In MIA PaCa-2 cells (human pancreatic carcinoma cell line), the phosphorylation of the CK2 biomarker CDC37 at S13 was almost completely inhibited in the presence of D11. This was observed both under normoxia and hypoxia. In the case of the human non-small cell lung carcinoma cell line, H1299, increasing amounts of D11 led to an inhibition of S380/T382/383 phosphorylation in PTEN, another biomarker for CK2 activity.

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A subnanomolar fluorescent probe for protein kinase CK2 interaction studies

Cited by 35 publications

References 40 publications

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

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