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

Roderer D, Hofnagel O, Benz R, Raunser SLaraia L, Garivet G, Foley DJ, 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 (2019). PNAS

doi: 10.1002/anie.201913712.

By using image-based morphological profiling in the cell painting assay the Waldmann lab discovered the autophagy inhibitor autoquin and its molecular mode of action. Autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. It also sequesters Fe2+ in lysosomes resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules.
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