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Phenotyping Reveals...
Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor
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Foley, Daniel J. (författare)
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Zinken, Sarah (författare)
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- Corkery, Dale (författare)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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Laraia, Luca (författare)
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Pahl, Axel (författare)
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- Wu, Yao-Wen, Professor (författare)
- Umeå universitet,Kemiska institutionen,Umeå Centre for Microbial Research (UCMR)
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Waldmann, Herbert (författare)
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(creator_code:org_t)
- 2020-04-21
- 2020
- Engelska.
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Ingår i: Angewandte Chemie International Edition. - : Wiley-VCH Verlagsgesellschaft. - 1433-7851 .- 1521-3773. ; 59:30
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Nyckelord
- alkaloids
- autophagy
- chemical biology
- inhibitors
- natural products
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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