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

Article Article scientifique Article Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability eng 2025-02-19 author Von Glasenapp Victoria Franziska 0009-0000-2413-7077 Department of Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,NCCR Chemical Biology, University of Geneva, Geneva, Switzerland. 837359 Département de physiologie cellulaire et métabolisme (PHYME) author Coelho de Almeida Ana Isabel 0000-0002-0756-0903 Department of Molecular and Cellular Biology, Faculty of Science, University of Geneva, Geneva, Switzerland. 402378 Département de biologie moléculaire et cellulaire (MOCEL) author Chang Dalu 0009-0003-2443-3265 NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.,Department of Organic Chemistry, Faculty of Science, University of Geneva, Geneva, Switzerland. 842153 author Gasic Ivana 0000-0002-4824-8174 Department of Molecular and Cellular Biology, Faculty of Science, University of Geneva, Geneva, Switzerland. 796323 Département de biologie moléculaire et cellulaire (MOCEL) author Winssinger Nicolas 0000-0003-1636-7766 NCCR Chemical Biology, University of Geneva, Geneva, Switzerland. nicolas.winssinger@unige.ch.,Department of Organic Chemistry, Faculty of Science, University of Geneva, Geneva, Switzerland. nicolas.winssinger@unige.ch. 769664 Département de chimie organique (CHIOR) author Gotta Monica 0000-0002-4336-7860 Department of Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. monica.gotta@unige.ch.,NCCR Chemical Biology, University of Geneva, Geneva, Switzerland. monica.gotta@unige.ch. 659510 Département de physiologie cellulaire et métabolisme (PHYME) 1599 10.1038/s41467-025-56746-5 39971898 2041-1723 PMC11840123 https://www.nature.com/articles/s41467-025-56746-5 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. Cell Cycle Proteins / antagonists & inhibitors Cell Cycle Proteins / metabolism Coumarins / chemistry Coumarins / pharmacology HeLa Cells Humans Light Mitosis / drug effects Polo-Like Kinase 1 Protein Kinase Inhibitors / pharmacology Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / metabolism Proto-Oncogene Proteins / antagonists & inhibitors Proto-Oncogene Proteins / metabolism Pteridines / pharmacology Dewey 540 Dewey 612 Dewey 570 Swiss National Science Foundation NCCR Chemical Biology - Visualisation and Control of Biological Processes Using Chemistry (phase III) 185898 CH Programmes Swiss National Science Foundation Regulation of cell division by stress granule components 204267 CH Projects Swiss National Science Foundation Chemical biology probes from natural product synthesis, artificial biochemical circuitry and antagomirs 188406 CH Projects Swiss National Science Foundation Tubulin Quantity Control and Microtubule Homeostasis 194312 CH Careers 36 Département de chimie organique 141 134 Département de physiologie cellulaire et métabolisme 21C 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 762 Groupe Winssinger 509 La division asymétrique 847 860 NCCR Chemical Biology https://yareta.unige.ch/archives/7622a143-61a3-4445-90f9-4a705d1fffd2 Nature communications 16 1 76783fe4-3757-4a80-b754-a09aeb3e7eaf Article (Published version) Public Article_scientifique_from_crossref.pdf 2114460 application/pdf CC BY-4.0 810736c21d74ceab55b5503a05079d2e6f1cb75ec77bd95dc481f6433cda6332 36a8fea5-439a-4918-82d4-ebc5b89b7a2d Supplemental data Public 41467_2025_56746_MOESM1_ESM.pdf 17614209 application/pdf 8605fae00e116a3da3b55db731a832dd4c3f2b79c3f093b4cf6663df2dbcc766 d0478b6d-3a17-46e2-8643-dba64b52c877 Supplemental data Public 41467_2025_56746_MOESM2_ESM.pdf 86316 application/pdf abce54839c45c0ea2261c571aa4f06a33cbebb4aedd8e235d4e707ee8aff662b d1ee605d-dd3a-45d0-a725-e12d7439ec8b Supplemental data Public 41467_2025_56746_MOESM3_ESM.avi 104126868 application/x-troff-msvideo e70bb6cdb4bc50426972bdc8993dbc6aa5f7343b80cc955f19504b07a825b680 582404f2-b5d7-4af2-9a6f-a7ed7f51d842 Supplemental data Public 41467_2025_56746_MOESM4_ESM.avi 104126868 application/x-troff-msvideo 1482b8b9987c371b63035631527d0c46f61459ea7c5743cae4a358f29f464b2b b47ea7f3-c1c5-44a0-bafd-1a05db1d1db7 Supplemental data Public 41467_2025_56746_MOESM5_ESM.avi 104126868 application/x-troff-msvideo 4465eebee90e86792a44c4b8cf2022276f551760b5fbaaa0a87cde3005e1b219 921566fb-1870-4507-a875-982941edf665 Supplemental data Public 41467_2025_56746_MOESM6_ESM.pdf 223873 application/pdf 27e882d90627d05b17dfa7a1ec7ff26b51804546573b6c4e2652b693206ad1ac 535828cd-9ba7-41b0-889c-484fc1d2a732 Supplemental data Public 41467_2025_56746_MOESM7_ESM.pdf 834952 application/pdf 84983bea1b4d7e552c8c06e1af52edd6ec78f78aa8e94c6edd5222d408207db4 openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

Title	Published in	Year	Views	Downloads

Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability	Nature communications	2025	176	76
Spatial and Temporal Control of Plk1 inhibition: Regulating Mitosis with Light		2024	387	3

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