Tipping the balance: synthesis and evaluation of centrinone-based degraders of polo-like kinase 4

Article Article scientifique Article Tipping the balance: synthesis and evaluation of centrinone-based degraders of polo-like kinase 4 eng 2026-05-29 author Kovacevic Andrej 0009-0007-9899-4486 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet Geneva Switzerland sascha.hoogendoorn@unige.ch. 986873 Chimie organique (groupe 8) (CHOR8) author Salim Aleksandar 0000-0002-8020-3355 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet Geneva Switzerland sascha.hoogendoorn@unige.ch. 963181 author Da Costa Horta Borges Crisálida 0009-0009-8370-0232 Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet 1 Geneva Switzerland. 957752 Département de physiologie cellulaire et métabolisme (PHYME) author Meraldi Patrick 0000-0001-9742-8756 Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet 1 Geneva Switzerland. 108140 Département de physiologie cellulaire et métabolisme (PHYME) author Hoogendoorn Sascha 0000-0002-1155-8697 Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet Geneva Switzerland sascha.hoogendoorn@unige.ch. 917221 Département de chimie organique (CHIOR) 10.1039/D5CB00315F 42220890 2633-0679 PMC13220175 https://xlink.rsc.org/?DOI=D5CB00315F Polo-like kinase 4 (PLK4) is a serine/threonine-protein kinase that plays a pivotal role in centriole biogenesis and, as such, represents a master regulator of centriole duplication. Due to its importance in cancer development and progression, PLK4 represents an attractive target for the development of novel therapeutics. Herein, we present a series of molecular degraders of PLK4, based on the highly selective PLK4 inhibitor centrinone, with the aim of targeting PLK4 for degradation <i>via</i> the ubiquitin-proteasome system. While all synthesized degraders retained low nanomolar binding affinities to the kinase domain of PLK4, large differences were found with respect to their ability to change cellular PLK4 levels. We uncover a complex pharmacological profile of the most potent degraders, D6 and D10, consisting of concomitant lowering of PLK4 levels through degradation, and enhancing PLK4 levels through inhibition of its autoregulation - dependent on its localization at the centrioles. Dewey 540 Dewey 612 European Commission Destination cilium: towards selective probing and perturbation of ciliary signaling 948750 DestCilia EU H2020 Swiss National Science Foundation Inhibitors of cilia and Hedgehog signaling: from phenotype to mechanistic understanding 189246 CH Swiss National Science Foundation Investigating the control and function of spindle microtubule dynamics 208052 CH Swiss National Science Foundation Modulation of ciliary signaling through targeted protein degradation 10000608 CH 36 Département de chimie organique 141 134 Département de physiologie cellulaire et métabolisme 21C false 1380 Groupe Hoogendoorn 579 Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) 922 https://doi.org/10.5281/zenodo.17738397 RSC chemical biology 94e4a499-24bf-4982-a94b-d60a3f928b47 Article (Published version) Public d5cb00315f-2.pdf 6589370 application/pdf CC BY-3.0 98f735ef263eb6598a33581954f5a24c2a4d70d4149f86a933784352a4a4efed 581eb532-ceea-4693-871d-603a4f64bedc Appendix Public CB-OLF-D5CB00315F-s001.pdf 32393821 application/pdf 34e02d74ac9429324ea6b4d83024cd598332cfc60f9a134a7ccd7c962fb88cd4 Vignette Public TOC.png 60194 image/png 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

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Tipping the balance: synthesis and evaluation of centrinone-based degraders of polo-like kinase 4	RSC chemical biology			2026	11	67

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Kovacevic, Andrej

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