Screening for inhibitors of protein phosphatases that induce mitotic cell death in cancer cells

To this day, cancer is a prevalent disease that accounts for a significant portion of the mortality that is seen in the modern world. The taxanes and vinca alkaloids play a prominent role in the treatment of many types of cancer. These molecules kill cancer cells in mitosis by chronicly activating the spindle assembly checkpoint (SAC) and subsequently inducing mitotic cell death (MCD). However, the clinical use of these molecules has two important limitations: first, they often lead to irreversible neuronal damage in the peripheral nerves which forces oncologists to abort the treatment, and secondly they only induce a mild chronic SAC activation, which limits their efficacy. The hypothesis of this project is that a stronger chronic SAC activation and thus more potent anti-cancer effect can be achieved by the specific inhibition of protein phosphatase 1 (PP1) holoenzymes that play a major role in mitosis and silencing of the SAC. Specific inhibition of this holoenzyme is possible with so-called protein-protein interaction inhibitors (iPPI's). The academia and industry is growing increasingly interested in these types of molecules because of their ability to achieve high specificity towards the inhibition of disease-related enzymes. To identify an inhibitor specific for a PP1 holoenzyme we will develop innovative high-throughput screening assays that are based on split-luciferase complementation technology. The compounds that are identified in this way will be characterized using a variety of biochemical and cell biological techniques. The molecules with the most promising pharmacological profile will be assayed for their oncotherapeutic potential and synergism with classic oncotherapeutics using relevant pre-clinical cancer models.