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.
Highlights
Tumor cells accumulate alterations that result in uncontrolled proliferation and genomic instability, loss of normal cell-cycle control being a hallmark of human cancer[1]
Their function still remains partially unknown, recent literature data support the hypothesis that some members of NIMA-related kinase (NEK) family may play a role in mitotic progression; in detail, NEK2, NEK6, NEK7 and NEK9 have been reported to contribute to the establishment of the microtubule based mitotic spindle[3,4,5]
Most of the functions described for NEK6 and NEK7 are very similar, the majority of NEK6 and NEK7 substrates identified to date are specific for one or other kinase[20]
Summary
Tumor cells accumulate alterations that result in uncontrolled proliferation and genomic instability, loss of normal cell-cycle control being a hallmark of human cancer[1]. The generation of anti-mitotic therapies would ideally target cell-cycle features that are distinctive for tumor cells, as genomic instability and/or defective checkpoints in mitosis Based on this assumption, the mitotic kinases governing centrosome dynamics and mitotic spindle function are potential targets for anticancer therapy[2]. Overexpression of NEK6 has been linked to many human diseases including liver, breast, lung, stomach, colon, larynx, ovary and prostate cancer[11,12,13,14,15,16], and in line with these findings, we recently showed that NEK6 is an independent unfavorable prognostic marker in ovarian cancer[11] Taken together these data indicate that the precise role in tumorigenesis remains unknown, NEK6 represents an attractive target for new anticancer therapies and inhibitors of NEK6 could be powerful compounds in the clinical setting. Cellular assays subsequently demonstrated antiproliferative activity for the same compound
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