2. Academic Validation
  3. Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

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

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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