Phenotyping reveals the targets of a pseudo-natural product autophagy inhibitor

Foley DJ, ZInken S, Corkery D, Laraia L, Pahl A, Wu Y, Waldmann H (2020) Angew Chem Int Ed Engl.

doi: 10.1002/anie.202000364

The Waldmann group has merged the Cinchona alkaloid scaffold with the indole ring-system to synthesise ‘indocinchona alkaloids’ via an efficient Pd-catalysed annulation. Phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the ‘azaquindoles’. Subsequent characterisation of the most potent compound, azaquindole-1, in the morphological “cell painting” assay, revealed that, in contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.

Design strategy to derive novel `indocinchona alkaloids´
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