Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor.
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.
['Foley|Daniel J|DJ|0000-0001-6221-3333', 'Zinken|Sarah|S|', 'Corkery|Dale|D|0000-0001-7930-0134', 'Laraia|Luca|L|0000-0001-6692-3412', 'Pahl|Axel|A|', 'Wu|Yao-Wen|YW|0000-0002-2573-8736', 'Waldmann|Herbert|H|0000-0002-9606-7247']
D001343:Autophagy D001688:Biological Products D002384:Catalysis D058546:Class III Phosphatidylinositol 3-Kinases D015195:Drug Design D004791:Enzyme Inhibitors D006801:Humans D061986:MCF-7 Cells D010165:Palladium
autophagy inhibitors natural products alkaloids chemical biology