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Phenotyping Reveals Targets of a Pseudo‐Natural‐Product Autophagy Inhibitor
Author(s) -
Foley Daniel J.,
Zinken Sarah,
Corkery Dale,
Laraia Luca,
Pahl Axel,
Wu YaoWen,
Waldmann Herbert
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202000364
Subject(s) - natural product , autophagy , alkaloid , phenotypic screening , chemistry , biochemistry , indole test , prenylation , computational biology , drug discovery , phenotype , biology , combinatorial chemistry , enzyme , stereochemistry , gene , apoptosis
Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34.