Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Yamada, Masahiro; Katsuma, Susumu; Adachi, Tomohiko; Hirasawa, Akira; Shiojima, Satoshi; Kadowaki, Tadashi; Okuno, Yasushi; Koshimizu, Taka-aki; Fujii, Shigeo; Sekiya, Yumiko; Miyamoto, Yohei; Tamura, Mina; Yumura, Wako; Nihei, Hiroshi; Kobayashi, Makio; Tsujimoto, Gozoh

doi:10.1073/pnas.0409818102

Cited by 77 publications

(55 citation statements)

References 30 publications

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“…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.…”

supporting

confidence: 50%

“…Since we have demonstrated that administration of CK2 inhibitors ameliorated the progression of GN, 5) we examined the in vivo effects of compound 13 on experimental GN. As with our previous study, 5) WKY rats were injected with anti-GBM antibodies to induce experimental anti-GBM GN.…”

Section: Compound 13 Suppresses the Progression Of Anti-gbm Gn In Vivomentioning

confidence: 99%

“…As with our previous study, 5) WKY rats were injected with anti-GBM antibodies to induce experimental anti-GBM GN. In contrast to the control rats, the anti-GBM antibody-injected rats developed severe proteinuria, with the level of urinary protein excretion increased almost 5-fold at day 7 ( Fig.…”

Section: Compound 13 Suppresses the Progression Of Anti-gbm Gn In Vivomentioning

confidence: 99%

“…To better understand the inhibitory activities of compound 13, we also included two well-known CK2 inhibitors, emodin and hematein, 5,12) in the kinase assay for comparison. The IC 50 value of compound 13 towards CK2α and CK2α′ are 0.068 µM and 0.059 µM in the presence of 95 µM ATP, respectively (Table 1).…”

Section: Compound 13 Is a Potent Ck2 Inhibitormentioning

confidence: 99%

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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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confidence: 50%

Section: Compound 13 Suppresses the Progression Of Anti-gbm Gn In Vivomentioning

confidence: 99%

Section: Compound 13 Suppresses the Progression Of Anti-gbm Gn In Vivomentioning

confidence: 99%

Section: Compound 13 Is a Potent Ck2 Inhibitormentioning

confidence: 99%

See 2 more Smart Citations

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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“…All cells, growing at a cell density of 5 · 10 5 cells mL -1 , were treated with or without 100 nmol L -1 DEX or 400 nmol L -1 PRD for 24 h. At 0 or 24 h total RNA isolated from each sample was reversetranscribed using the Quantitect reverse transcription kit (Qiagen, Valencia, CA, USA) and this was analyzed by quantitative PCR using ABsolute QPCR SYBR Green Mixes (ABgene, Surrey, UK) in a DNA Engine Opticon2 System (Biorad, Hercules, CA, USA) as described previously (Yamada et al 2005). GAPDH was used to standardize the mRNA levels of target genes.…”

Section: Qrt-pcrmentioning

confidence: 99%

Glucocorticoid-induced granzyme A expression can be used as a marker of glucocorticoid sensitivity for acute lymphoblastic leukemia therapy

et al. 2007

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Structure‐Activity Relationships of Pyrazine‐Based CK2 Inhibitors: Synthesis and Evaluation of 2,6‐Disubstituted Pyrazines and 4,6‐Disubstituted Pyrimidines

Suzuki

Jérôme

Hara

et al. 2008

Archiv der Pharmazie

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Structurally related to the known CK2 inhibitors, 2,6-disubstituted pyrazine and 4,6-disubstituted pyrimidine derivatives were synthesized and their inhibitory activities toward CK2alpha and CK2alpha' were evaluated. Structure-activity relationship study has revealed that several pyrazine derivatives bearing a (pyrrol-3-yl)acetic acid and a monosubstituted aniline possess potent inhibitory activities.

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Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis

Cited by 77 publications

References 30 publications

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

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

Glucocorticoid-induced granzyme A expression can be used as a marker of glucocorticoid sensitivity for acute lymphoblastic leukemia therapy

Structure‐Activity Relationships of Pyrazine‐Based CK2 Inhibitors: Synthesis and Evaluation of 2,6‐Disubstituted Pyrazines and 4,6‐Disubstituted Pyrimidines

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