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

Journal: Scientific reports 2019;8(1):16047

PMID: 30375481

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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 IC 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.

Address: Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy.; Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.; Institute of Biochemistry and Clinical Biochemistry - Università Cattolica del Sacro Cuore, Rome, Italy.; Gynecologic and Obstetric Clinic, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.; Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy.; Institute of Chemistry of Molecular Recognition (ICRM) - CNR, Rome, Italy. [email protected].

DOI: 10.1038/s41598-018-34471-y

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MeSH Terms: Amino Acid Sequence, Antineoplastic Agents, Binding Sites, Cell Line, Tumor, Drug Discovery, Enzyme Activation, Humans, Inhibitory Concentration 50, Ligands, Molecular Conformation, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, NIMA-Related Kinases, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Structure-Activity Relationship