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

  • Sci Rep. 2018 Oct 30;8(1):16047. doi: 10.1038/s41598-018-34471-y.
Marta De Donato  1  2 ,  Benedetta Righino  3 ,  Flavia Filippetti  1  2 ,  Alessandra Battaglia  1 ,  Marco Petrillo  1  4 ,  Davide Pirolli  5 ,  Giovanni Scambia  1  2 ,  Maria Cristina De Rosa  6 ,  Daniela Gallo  1  2
Affiliations
  • 1. Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 2. Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
  • 3. Institute of Biochemistry and Clinical Biochemistry - Università Cattolica del Sacro Cuore, Rome, Italy.
  • 4. Gynecologic and Obstetric Clinic, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
  • 5. Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy.
  • 6. Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy. [email protected].
PMID: 30375481 DOI: 10.1038/s41598-018-34471-y
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.

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