Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34. Issue 28 (12th June 2017)

• Record Type: Journal Article
• Authors: 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, Yao‐Wen; Engel, Julian
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 28(2017)
• Page Start: 8153
• Page End: 8157
• Publication Date: 2017-06-12
• Subjects: aminopyrimidines -- autophagy -- kinase inhibitors -- phenotypic assays -- VPS34; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201703738
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : PI(3)KC(3)ing autophagy apart : Phenotypic screening followed by target identification reveals a novel autophagy‐inhibiting chemotype that inhibits the lipid kinase PIK3C3 (VPS34) with high potency, disrupting autophagosome biogenesis.