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Pharmaceuticals 2018, 11(1), 23; https://doi.org/10.3390/ph11010023

A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors

1
Institut für Biochemie, Department für Chemie, Universität zu Köln, Zülpicher Straße 47, D-50674 Köln, Germany
2
Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany
3
Medizinische Biochemie und Molekularbiologie, Universität des Saarlandes, Kirrberger Str., Geb. 44, D-66421 Homburg, Germany
4
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Received: 23 November 2017 / Revised: 13 February 2018 / Accepted: 14 February 2018 / Published: 17 February 2018
(This article belongs to the Collection Choices of the Journal)
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Abstract

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency. View Full-Text
Keywords: human protein kinase CK2; dibenzofuran; tight binding inhibitor; crystal structure; π-halogen bond; apoptosis induction human protein kinase CK2; dibenzofuran; tight binding inhibitor; crystal structure; π-halogen bond; apoptosis induction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Schnitzler, A.; Gratz, A.; Bollacke, A.; Weyrich, M.; Kuckländer, U.; Wünsch, B.; Götz, C.; Niefind, K.; Jose, J. A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors. Pharmaceuticals 2018, 11, 23.

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