title: Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition.
abstract: Lysosomal protein degradation via autophagy strictly regulates cellular protein homoeostasis. Herein we performed high-content screening to identify compounds that inhibit autophagy pathways. We obtained 11 hit compounds and performed cluster analysis using cellular morphological information. Vacuolin-1, which induces the formation of giant vacuoles and is a target unknown compound, clustered with the known PIKfyve inhibitor YM201636. We further confirmed that vacuolin-1 is a potent PIKfyve inhibitor, and we finally concluded that PIKfyve inhibitors are novel chemical tools for regulating autophagy.
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sano
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kazetani
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Funata
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.affiliation: BioMolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Fujisawa, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C503870:vacuolin-1; C492139:PIKFYVE protein, human
keywords: PIKfyve; autophagy; vacuolin-1