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A High-Content, Cell-Based Screen Identifies Micropolyin, A New Inhibitor of Microtubule Dynamics

Authors

  • Manu De Rycker,

    1. Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
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  • Laurent Rigoreau,

    1. Cancer Research Technology, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK
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  • Sarah Dowding,

    1. Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
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  • Peter J. Parker

    Corresponding author
    1. Protein Phosphorylation Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
    2. Division of Cancer Studies King’s College London, New Hunt’s House, Guy’s Hospital, St Thomas Street, London SE1 1UL, UK
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*Peter J. Parker, peter.parker@cancer.org.uk

Abstract

High-content cell-based screens provide a powerful tool to identify new chemicals that interfere with complex biological processes. Here, we describe the identification of a new inhibitor of microtubule dynamics (micropolyin) using a high-content screen. Integrated high-resolution imaging allowed for fast selection of hits and progression to target identification. Treatment of cells with micropolyin efficiently causes a pro-metaphase arrest, with abnormal spindle morphology and with the spindle assembly checkpoint activated. The arrest appears to result from interference of micropolyin with microtubule dynamics. We show in vitro that tubulin is indeed the target of micropolyin and that micropolyin inhibits microtubule polymerization. Our results demonstrate the power of high-content image- and cell-based screening approaches to identify potential new drug candidates. As our approach is unbiased, it should allow for discovery of new targets that may otherwise be overlooked.

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