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

Daniel J. Foley, Sarah Zinken, Dale Corkery, Luca Laraia, Axel Pahl, Yaowen Wu, Herbert Waldmann*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Principles for the design and synthesis of novel bioactive compounds can efficiently draw from insights gained into natural product (NP) structure and bioactivity, including complexity-to-diversity approaches and biology-oriented synthesis. Pseudo-natural product design goes beyond these principles, and combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, yet 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. We have merged the Cinchona alkaloid scaffold with the indole ring-system to synthesise 'indocinchona alkaloids' via an efficient Pd-catalysed annulation. Exploration of indocinchona alkaloid bioactivity in 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, guided target identification efforts which revealed that, in contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.
Original languageEnglish
JournalAngewandte Chemie International Edition
Volume59
Issue number30
Pages (from-to)12470-12476
ISSN1433-7851
DOIs
Publication statusPublished - 2020

Keywords

  • Pseudo-natural products
  • Autophagy
  • Phenotyping
  • Alkaloids
  • Inhibitors
  • Chemical biology

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