Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34

Lucas Robke, Luca Laraia, Marjorie A. Carnero Corrales, Georgios Konstantinidis, Makoto Muroi, Andre Richters, Michael Winzker, Tobias Engbring, Stefano Tomassi, Nobumoto Watanabe, Hiroyuki Osada, Daniel Rauh, Herbert Waldmann, Yao-Wen Wu, Julian Engel

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.
Original languageEnglish
JournalAngewandte chemie-international edition
Volume56
Issue number28
Pages (from-to)8153-8157
ISSN1433-7851
DOIs
Publication statusPublished - 2017
Externally publishedYes

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