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Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor
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2020 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, p. 5721-5729Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2020. Vol. 59, p. 5721-5729
Keywords [en]
autophagy, cell painting, lysosome, proteomics, target identification
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-168237DOI: 10.1002/anie.201913712ISI: 000508991300001PubMedID: 31769920Scopus ID: 2-s2.0-85078676260OAI: oai:DiVA.org:umu-168237DiVA, id: diva2:1394088
Available from: 2020-02-18 Created: 2020-02-18 Last updated: 2023-09-05Bibliographically approved

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Corkery, DaleWu, Yao-Wen

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CiteExportLink to record
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