Therapeutic strategies targeting cell cycle in cancer have in general failed in the clinic since the drugs have lacked the therapeutic index required to achieve a robust response against cancer cells with little or no cytotoxic effect on normal cells. NEK6 kinase, which is implicated in cell cycle control, has recently emerged as an attractive target for the development of novel anticancer drugs with enhanced therapeutic index. With the support of computational chemistry simulations (structure-based virtual screening and pharmacophore modelling) we discovered and patented few small molecules able to inhibit the activity of NEK6 kinase. Our compounds displayed selectivity, antiproliferative activity against a panel of human cancer cell lines and exhibited a synergistic effect with cisplatin and paclitaxel, thus supporting a possible use for personalized oncological therapy.
Past agents designed to block cell cycle specifically during mitosis, such as MTAs or inhibitors against cyclin-dependent kinases, aurora kinases, and Polo-like Kinase 1, have yielded disappointing clinical results due to non-malignant cell cytotoxicity. Evidences support the hypothesis that NEK6 inhibition selectively induce the death of neoplastic cells, while saving normal cells. Identified KEK6 inhibitors emerged as hit compounds for the development of novel anticancer agents, opening the possibility of new therapeutic strategies with improved therapeutic index in personalized oncology. This would allow advantages to the pharmaceutical industry (increased efficiency and reduced costs, product differentiation in the market place) and to patients and clinicians (higher probability of desired outcome, low probability of side effects). Virtual screening of commercial libraries of compounds, herein used, allows an important reduction of costs of the chemicals.
Italy, Europe, USA