Disruption of endocytosis through chemical inhibition of clathrin heavy chain function PMID: 31011214

ADC Targets in Oncology

2026-04-10

Disruption of endocytosis through chemical inhibition of clathrin heavy chain function

Nat Chem Biol. 2019 Jun;15(6):641-649. doi: 10.1038/s41589-019-0262-1.

Wim Dejonghe ^# ¹ ² ³ , Isha Sharma ^# ¹ ² , Bram Denoo ⁴ , Steven De Munck ⁵ ⁶ , Qing Lu ¹ ² , Kiril Mishev ¹ ² ⁷ , Haydar Bulut ⁸ , Evelien Mylle ¹ ² , Riet De Rycke ¹ ² ⁹ , Mina Vasileva ¹⁰ , Daniel V Savatin ¹ ² , Wim Nerinckx ¹¹ ¹² , An Staes ¹¹ ¹³ , Andrzej Drozdzecki ¹⁴ ¹⁵ , Dominique Audenaert ¹⁴ ¹⁵ , Klaas Yperman ¹ ² , Annemieke Madder ⁴ , Jiří Friml ¹⁰ , Daniël Van Damme ¹ ² , Kris Gevaert ¹¹ ¹³ , Volker Haucke ¹⁶ , Savvas N Savvides ⁵ ⁶ , Johan Winne ⁴ , Eugenia Russinova ¹⁷ ¹⁸

Affiliations

1. Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium.
2. Center for Plant Systems Biology, VIB, Ghent, Belgium.
3. Department of Botany and Plant Sciences, Institute of Integrative Genome Biology, University of California, Riverside, CA, USA.
4. Department of Organic and Macromolecular Chemistry, Ghent University, Ghent, Belgium.
5. Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
6. Unit for Structural Biology, Center for Inflammation Research, VIB, Ghent, Belgium.
7. Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, Sofia, Bulgaria.
8. Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
9. Ghent University Expertise Centre for Transmission Electron Microscopy and VIB BioImaging Core, Ghent, Belgium.
10. Institute of Science and Technology, Klosterneuburg, Austria.
11. Center for Medical Biotechnology, VIB, Ghent, Belgium.
12. Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.
13. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
14. VIB Screening Core, Ghent, Belgium.
15. Expertise Centre for Bioassay Development and Screening, Ghent University, Ghent, Belgium.
16. Department of Molecular Pharmacology and Cell Biology, Leibniz Research Institute for Molecular Pharmacology, Berlin, Germany.
17. Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium. [email protected].
18. Center for Plant Systems Biology, VIB, Ghent, Belgium. [email protected].
# Contributed equally.

Abstract

Clathrin-mediated endocytosis (CME) is a highly conserved and essential cellular process in eukaryotic cells, but its dynamic and vital nature makes it challenging to study using classical genetics tools. In contrast, although small molecules can acutely and reversibly perturb CME, the few chemical CME inhibitors that have been applied to Plants are either ineffective or show undesirable side effects. Here, we identify the previously described endosidin9 (ES9) as an inhibitor of clathrin heavy chain (CHC) function in both Arabidopsis and human cells through affinity-based target isolation, in vitro binding studies and X-ray crystallography. Moreover, we present a chemically improved ES9 analog, ES9-17, which lacks the undesirable side effects of ES9 while retaining the ability to target CHC. ES9 and ES9-17 have expanded the chemical toolbox used to probe CHC function, and present chemical scaffolds for further design of more specific and potent CHC inhibitors across different systems.