Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor

Luca Laraia, Guillaume Garivet, Daniel J. Foley, Nadine Kaiser, Sebastian Müller, Sarah Zinken, Thomas Pinkert, Julian Wilke, Dale Corkery, Axel Pahl, Sonja Sievers, Petra Janning, Christoph Arenz, Yaowen Wu, Raphaël Rodriguez, Herbert Waldmann*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Chemical proteomics is widely applied in small-molecule target identification. However, in general it does not identify non-protein small-molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe2+ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology.

Original languageEnglish
JournalAngewandte Chemie - International Edition
Volume59
Issue number14
Pages (from-to)5721-5729
ISSN1433-7851
DOIs
Publication statusPublished - 2020

Keywords

  • autophagy
  • cell painting
  • lysosome
  • proteomics
  • target identification

Cite this

Laraia, L., Garivet, G., Foley, D. J., Kaiser, N., Müller, S., Zinken, S., Pinkert, T., Wilke, J., Corkery, D., Pahl, A., Sievers, S., Janning, P., Arenz, C., Wu, Y., Rodriguez, R., & Waldmann, H. (2020). Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor. Angewandte Chemie - International Edition, 59(14), 5721-5729. https://doi.org/10.1002/anie.201913712