caa a22 4500 606236325 CHVBK 20210128101247.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s11010-015-2433-z doi (NATIONALLICENCE)springer-10.1007/s11010-015-2433-z Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library [Elektronische Daten] [Barbara Guerra, Jennifer Hochscherf, Nina Jensen, Olaf-Georg Issinger] 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 49nM. 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. Springer Science+Business Media New York, 2015 Protein kinase CK2 nationallicence Kinase inhibitors nationallicence Protein phosphorylation nationallicence Biomarkers nationallicence PTEN nationallicence CDC37 nationallicence Guerra Barbara Department of Biochemistry and Molecular Biology, Biomedical Research Group, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark aut Hochscherf Jennifer KinaseDetect ApS, Skovvej 22, 6340, Kruså, Denmark aut Jensen Nina KinaseDetect ApS, Skovvej 22, 6340, Kruså, Denmark aut Issinger Olaf-Georg Department of Biochemistry and Molecular Biology, Biomedical Research Group, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 406/1-2(2015-08-01), 151-161 0300-8177 406:1-2<151 2015 406 11010 https://doi.org/10.1007/s11010-015-2433-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2433-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Guerra Barbara Department of Biochemistry and Molecular Biology, Biomedical Research Group, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark aut NATIONALLICENCE 700 1- Hochscherf Jennifer KinaseDetect ApS, Skovvej 22, 6340, Kruså, Denmark aut NATIONALLICENCE 700 1- Jensen Nina KinaseDetect ApS, Skovvej 22, 6340, Kruså, Denmark aut NATIONALLICENCE 700 1- Issinger Olaf-Georg Department of Biochemistry and Molecular Biology, Biomedical Research Group, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 406/1-2(2015-08-01), 151-161 0300-8177 406:1-2<151 2015 406 11010