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Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34
Author(s) -
Robke Lucas,
Laraia Luca,
Carnero Corrales Marjorie A.,
Konstantinidis Georgios,
Muroi Makoto,
Richters André,
Winzker Michael,
Engbring Tobias,
Tomassi Stefano,
Watanabe Nobumoto,
Osada Hiroyuki,
Rauh Daniel,
Waldmann Herbert,
Wu YaoWen,
Engel Julian
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201703738
Subject(s) - autophagy , microbiology and biotechnology , kinase , cytosol , phenotype , biology , regulator , lipid metabolism , chemistry , biochemistry , enzyme , gene , apoptosis
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.