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

  • Angew Chem Int Ed Engl. 2017 Jul 3;56(28):8153-8157. doi: 10.1002/anie.201703738.
Lucas Robke  1  2 ,  Luca Laraia  1 ,  Marjorie A Carnero Corrales  1  2 ,  Georgios Konstantinidis  3 ,  Makoto Muroi  4  5 ,  André Richters  2 ,  Michael Winzker  1  2 ,  Tobias Engbring  2 ,  Stefano Tomassi  2 ,  Nobumoto Watanabe  5  6 ,  Hiroyuki Osada  4  5 ,  Daniel Rauh  2 ,  Herbert Waldmann  1  2 ,  Yao-Wen Wu  3 ,  Julian Engel  2
Affiliations
  • 1. Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.
  • 2. Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • 3. Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
  • 4. Chemical Biology Research Group, RIKEN CSRS, 2-1, Hirosawa, Wako, Saitama, 351-0198, Japan.
  • 5. RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN CSRS, 2-1, Hirosawa, Wako, Saitama, 351-0198, Japan.
  • 6. Bio-Active Compounds Discovery Research Unit, RIKEN CSRS, 2-1, Hirosawa, Wako, Saitama, 351-0198, Japan.
PMID: 28544137 DOI: 10.1002/anie.201703738
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.

Keywords
VPS34; aminopyrimidines; autophagy; kinase inhibitors; phenotypic assays.
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