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Image‐Based Morphological Profiling Identifies a Lysosomotropic, Iron‐Sequestering Autophagy Inhibitor
Author(s) -
Laraia Luca,
Garivet Guillaume,
Foley Daniel J.,
Kaiser Nadine,
Müller Sebastian,
Zinken Sarah,
Pinkert Thomas,
Wilke Julian,
Corkery Dale,
Pahl Axel,
Sievers Sonja,
Janning Petra,
Arenz Christoph,
Wu Yaowen,
Rodriguez Raphaël,
Waldmann Herbert
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201913712
Subject(s) - autophagy , mode of action , microbiology and biotechnology , small molecule , proteomics , profiling (computer programming) , programmed cell death , mechanism of action , chemistry , lysosome , biology , computational biology , biochemistry , enzyme , apoptosis , computer science , in vitro , gene , operating system
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 Fe 2+ 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.