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

被引：0
作者：
von Glasenapp, Victoria [1 ,2 ]
Almeida, Ana C. [3 ]
Chang, Dalu [2 ,4 ]
Gasic, Ivana [3 ]
Winssinger, Nicolas [2 ,4 ]
Gotta, Monica [1 ,2 ]
机构：
[1] Univ Geneva, Fac Med, Dept Physiol & Metab, Geneva, Switzerland
[2] Univ Geneva, NCCR Chem Biol, Geneva, Switzerland
[3] Univ Geneva, Fac Sci, Dept Mol & Cellular Biol, Geneva, Switzerland
[4] Univ Geneva, Fac Sci, Dept Organ Chem, Geneva, Switzerland
来源：
NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期
基金：
瑞士国家科学基金会;
关键词：
SMALL-MOLECULE INHIBITOR; POLO; KINASE; PHOTOPHARMACOLOGY; PHOSPHORYLATION; ACTIVATION; MECHANISMS; CHEMISTRY; BI-2536;
D O I：
10.1038/s41467-025-56746-5
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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.
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页数：12
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