Emergence of protein kinase CK2 as a key target in cancer therapy

Trembley, Janeen H.; Chen, Zhong; Unger, Gretchen M.; Slaton, Joel W.; Kren, Betsy T.; Waes, Carter Van; Ahmed, Khalil

doi:10.1002/biof.96

Cited by 179 publications

(171 citation statements)

References 96 publications

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“…CK2 has now emerged as a relevant therapeutic target for the treatment of cancer (e.g. prostate, mammary gland, lung, kidney, hematologic malignancies) [9]. Indeed, diverse strategies are developed to target CK2 [10], and to synthesize highly specific, selective and cell-permeable inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Guillon¹,

Borgne²,

Rimbault³

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tHerein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC 50 in the microand sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl) amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC 50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Guillon¹,

Borgne²,

Rimbault³

et al. 2013

European Journal of Medicinal Chemistry

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“…The kinase is highly pleiotropic, with more than 300 substrates identified, and interacts with multiple signaling pathways (Meggio and Pinna, 2003;Duncan and Litchfield, 2008;Ruzzene and Pinna, 2010). CK2 kinase is considered one of the "master regulators" of the cell, playing a major role in processes related to cell growth, proliferation, death, and survival (Trembley et al, 2010). The kinase is constitutively active and ubiquitously expressed in all eukaryotes (Duncan and Litchfield, 2008).…”

Section: Introductionmentioning

confidence: 99%

Casein Kinase 2α Regulates Multidrug Resistance-Associated Protein 1 Function via Phosphorylation of Thr249

et al. 2012

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We have shown previously that the function of Ycf1p, yeast ortholog of multidrug resistance-associated protein 1 (MRP1), is regulated by yeast casein kinase 2␣ (Cka1p) via phosphorylation at Ser251. In this study, we explored whether casein kinase 2␣ (CK2␣), the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semiconserved site Thr249. Knockdown of CK2␣ in MCF7-derived cells expressing MRP1 [MRP1 CK2␣(Ϫ)] resulted in increased doxorubicin sensitivity. MRP1-dependent transport of leukotriene C 4 and estradiol-17␤-D-glucuronide into vesicles derived from MRP1 CK2␣(Ϫ) cells was decreased compared with MRP1 vesicles. Moreover, mutation of Thr249 to alanine (MRP1-T249A) also resulted in decreased MRP1-dependent transport, whereas a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings, showing increased intracellular doxorubicin accumulation in MRP1 CK2␣(Ϫ) and MRP1-T249A cells compared with MRP1 cells. Inhibition of CK2 kinase by 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2␣(Ϫ), MRP1-T249A, or MRP1-T249E cells, suggesting that CK2␣ regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2␣ and MRP1 interact physically, and recombinant CK2 phosphorylates MRP1-derived peptide in vitro in a Thr249-dependent manner, whereas knockdown of CK2␣ results in decreased phosphorylation at MRP1-Thr249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin and increased doxorubicin cytotoxicity. This study supports a model in which CK2␣ potentiates MRP1 function via direct phosphorylation of Thr249.

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“…17) It was reported to be implicated in a series of physiological and pathological processes, including various cancers, 18) bone formation, 19) mouse globozoospermia, 15) embryonic morphogenesis, 20) and chronic intestinal inammation. 21) We have previously identified CK2 as a GN-related gene and indicated that CK2 could be a therapeutic target for treating GN.…”

Section: Discussionmentioning

confidence: 99%

The Effects of a Selective CK2 Inhibitor on Anti-glomerular Basement Membrane Glomerulonephritis in Rats

Shi

Liu

Xiao

et al. 2015

Biological & Pharmaceutical Bulletin

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Protein kinase CK2 ("casein kinase II") is a protein serine/threonine kinase that plays critical roles in biological processes such as cell growth, cell cycle progression, and apoptosis. So far, we have identified that one catalytic isozyme of CK2, CK2α, is over-expressed in the kidney during the progression of glomerulonephritis (GN). Moreover, we have shown that in vivo inhibition of CK2 by administration of CK2 inhibitors was effective in the treatment of experimental GN. Hence the development of potent CK2 inhibitors should be considered in therapeutic strategies for GN. In the present study we identified compound 13, a pyrazine derivative, as a potent CK2 inhibitor. By performing enzyme kinetics analysis in vitro, we characterized the inhibition of compound 13 toward each CK2 catalytic isozyme. Furthermore, in vivo, we demonstrated that compound 13 is effective in attenuating proteinuria, decreasing the enhanced level of blood urea nitrogen and serum creatinine, and ameliorating glomerular crescent formation in an experimental GN rat model. On the other hand, cellular apoptosis was detected in the rat testis following administration of compound 13. This study provides clues for new strategies for developing applicable compounds into CK2-targeted GN treatments.Key words protein kinase CK2; glomerulonephritis (GN); CK2 inhibitor; testicular toxicity Protein kinase CK2 (formerly called "casein kinase 2") is a serine/threonine kinase ubiquitously distributed in eukaryotic organisms. CK2 phosphorylates more than 300 proteins, 1) and its roles in cells are various, including cell proliferation, cell growth, cell division, and cell apoptosis.2) The CK2 holoenzyme in mammals exists predominantly as a heterotetramer composed of two catalytic subunits (α and/or α′) and two regulatory subunits (β). The two catalytic isozymes of CK2, CK2α and CK2α′, have been well characterized. CK2α and CK2α′ exhibit approximately 90% identity in their catalytic domains, even though they arise from different chromosomes.2) Although they may display similar enzymatic properties (including turnover rates and substrate specificity) in vitro, the two isozymes may play different roles in vivo, since CK2α is widely distributed in various tissues, whereas CK2α′ is mainly expressed in the brain and testis.3) In a report, the deficiency of CK2α in mice caused embryonic lethality, while the knockout of CK2α′ in mice induced spermatocytes to undergo apoptosis and the surviving spermatozoa to exhibit abnormal morphology. 4) Hence, CK2α and CK2α′ may have distinct functions.We have previously identified CK2α, but not CK2α′, as a glomerulonephritis (GN)-related gene using cDNA microarray analysis. 5) In the same study, we observed that administration of either antisense oligodeoxynucleotide against CK2α or low molecular weight CK2 inhibitors effectively prevented the progression of renal dysfunction. Based on this background, we focused on developing novel CK2 inhibitors as a therapeutic agent for GN. We have synthesized a series of pyrazine deriva...

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Emergence of protein kinase CK2 as a key target in cancer therapy

Cited by 179 publications

References 96 publications

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Casein Kinase 2α Regulates Multidrug Resistance-Associated Protein 1 Function via Phosphorylation of Thr249

The Effects of a Selective CK2 Inhibitor on Anti-glomerular Basement Membrane Glomerulonephritis in Rats

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