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Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability

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  • Victoria Glasenapp

    (University of Geneva
    University of Geneva)

  • Ana C. Almeida

    (University of Geneva)

  • Dalu Chang

    (University of Geneva
    University of Geneva)

  • Ivana Gasic

    (University of Geneva)

  • Nicolas Winssinger

    (University of Geneva
    University of Geneva)

  • Monica Gotta

    (University of Geneva
    University of Geneva)

Abstract

The ability to control the activity of kinases spatially and temporally is essential to elucidate the role of signalling pathways in development and physiology. Progress in this direction has been hampered by the lack of tools to manipulate kinase activity in a highly controlled manner in vivo. Here we report a strategy to modify BI2536, the well characterized inhibitor of the conserved and essential mitotic kinase Polo-like kinase 1 (Plk1). We introduce the same coumarin photolabile protecting group (PPG) at two positions of the inhibitor. At one position, the coumarin prevents the interaction with Plk1, at the second it masks an added carboxylic acid, important for cellular retention. Exposure to light results in removal of both PPGs, leading to the activation of the inhibitor and its trapping inside cells. We demonstrate the efficacy of the caged inhibitor in three-dimensional spheroid cultures: by uncaging it with a single light pulse, we can inhibit Plk1 and arrest cell division, a highly dynamic process, with spatio-temporal control. Our design can be applied to other small molecules, providing a solution to control their activity in living cells with unprecedented precision.

Suggested Citation

  • Victoria Glasenapp & Ana C. Almeida & Dalu Chang & Ivana Gasic & Nicolas Winssinger & Monica Gotta, 2025. "Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56746-5
    DOI: 10.1038/s41467-025-56746-5
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    References listed on IDEAS

    as
    1. André Nadler & Dmytro A. Yushchenko & Rainer Müller & Frank Stein & Suihan Feng & Christophe Mulle & Mario Carta & Carsten Schultz, 2015. "Exclusive photorelease of signalling lipids at the plasma membrane," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    2. Owen Addis Jones & Ankana Tiwari & Tomisin Olukoga & Alex Herbert & Kok-Lung Chan, 2019. "PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    3. Eric Lindberg & Simona Angerani & Marcello Anzola & Nicolas Winssinger, 2018. "Luciferase-induced photoreductive uncaging of small-molecule effectors," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    4. James A. Cornwell & Adrijana Crncec & Marwa M. Afifi & Kristina Tang & Ruhul Amin & Steven D. Cappell, 2023. "Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal," Nature, Nature, vol. 619(7969), pages 363-370, July.
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