A π-halogen bond of dibenzofuranones with the gatekeeper Phe113 in human protein kinase CK2 leads to potent tight binding inhibitors
| Autor: | Claudia Götz, Karsten Niefind, Joachim Jose, Michael Weyrich, Bernhard Wünsch, Uwe Kuckländer, Andreas Gratz, Andre Bollacke, Alexander Schnitzler |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
crystal structure Stereochemistry Substituent lcsh:Medicine lcsh:RS1-441 Pharmaceutical Science Article lcsh:Pharmacy and materia medica 03 medical and health sciences chemistry.chemical_compound human protein kinase CK2 Drug Discovery LNCaP Transferase π-halogen bond heterocyclic compounds Viability assay tight binding inhibitor chemistry.chemical_classification Halogen bond Chemistry lcsh:R dibenzofuran apoptosis induction Amino acid Dibenzofuran 030104 developmental biology Apoptosis Molecular Medicine |
| Zdroj: | 'Pharmaceuticals ', vol: 11, pages: 23-1-23-24 (2018) Pharmaceuticals Pharmaceuticals, Vol 11, Iss 1, p 23 (2018) Pharmaceuticals; Volume 11; Issue 1; Pages: 23 |
| ISSN: | 1424-8247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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