The NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), which is implicated in cell cycle control and plays significant roles in tumorigenesis, is an attractive target for the development of novel anti-cancer drugs. Here we describe the discovery of a potent ATP site-directed inhibitor of NEK6 identified by virtual screening, adopting both structure- and ligand-based techniques. Using a homology-built model of NEK6 as well as the pharmacophoric features of known NEK6 inhibitors we identified novel binding scaffolds. Twenty-five compounds from the top ranking hits were subjected to in vitro kinase assays. The best compound, i.e. compound 8 ((5Z)-2-hydroxy-4-methyl-6-oxo-5-[(5-phenylfuran-2-yl)methylidene]-5,6-dihydropyridine-3-carbonitrile), was able to inhibit NEK6 with low micromolar IC50 value, also displaying antiproliferative activity against a panel of human cancer cell lines. Our results suggest that the identified inhibitor can be used as lead candidate for the development of novel anti-cancer agents, thus opening the possibility of new therapeutic strategies.

De Donato, M., Righino, B., Filippetti, F., Battaglia, A., Petrillo, M., Pirolli, D., Scambia, G., De Rosa, M. C., Gallo, D., Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6, <<SCIENTIFIC REPORTS>>, 2018; 8 (1): 1-13. [doi:10.1038/s41598-018-34471-y] [http://hdl.handle.net/10807/135043]

Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Righino, Benedetta;Filippetti, Flavia;Petrillo, Marco;Pirolli, Davide;Scambia, Giovanni;De Rosa, Maria Cristina;
2018

Abstract

The NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), which is implicated in cell cycle control and plays significant roles in tumorigenesis, is an attractive target for the development of novel anti-cancer drugs. Here we describe the discovery of a potent ATP site-directed inhibitor of NEK6 identified by virtual screening, adopting both structure- and ligand-based techniques. Using a homology-built model of NEK6 as well as the pharmacophoric features of known NEK6 inhibitors we identified novel binding scaffolds. Twenty-five compounds from the top ranking hits were subjected to in vitro kinase assays. The best compound, i.e. compound 8 ((5Z)-2-hydroxy-4-methyl-6-oxo-5-[(5-phenylfuran-2-yl)methylidene]-5,6-dihydropyridine-3-carbonitrile), was able to inhibit NEK6 with low micromolar IC50 value, also displaying antiproliferative activity against a panel of human cancer cell lines. Our results suggest that the identified inhibitor can be used as lead candidate for the development of novel anti-cancer agents, thus opening the possibility of new therapeutic strategies.
Inglese
De Donato, M., Righino, B., Filippetti, F., Battaglia, A., Petrillo, M., Pirolli, D., Scambia, G., De Rosa, M. C., Gallo, D., Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6, <<SCIENTIFIC REPORTS>>, 2018; 8 (1): 1-13. [doi:10.1038/s41598-018-34471-y] [http://hdl.handle.net/10807/135043]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/135043
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