期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 406, 期 1-2, 页码 151-161出版社
SPRINGER
DOI: 10.1007/s11010-015-2433-z
关键词
Protein kinase CK2; Kinase inhibitors; Protein phosphorylation; Biomarkers; PTEN; CDC37
类别
资金
- Danish Council for Independent Research-Natural Sciences [1323-00212A]
- Danish Cancer Society [252-1109-210]
- Danish Research Council [21-04-0517]
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 alpha and alpha'. The IC50 values for the CK2 alpha and CK2 alpha' 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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