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

Marta De Donato, Benedetta Righino, Flavia Filippetti, Alessandra Battaglia, Marco Petrillo, Davide Pirolli, Giovanni Scambia, Maria Cristina De Rosa, Daniela Gallo

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number16047
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • General

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    De Donato, M., Righino, B., Filippetti, F., Battaglia, A., Petrillo, M., Pirolli, D., Scambia, G., De Rosa, M. C., & Gallo, D. (2018). Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6. Scientific Reports, 8(1), [16047]. https://doi.org/10.1038/s41598-018-34471-y