A selective PIKfyve inhibitor blocks PtdIns(3,5)P(2) production and disrupts endomembrane transport and retroviral budding

EMBO Rep. 2008 Feb;9(2):164-70. doi: 10.1038/sj.embor.7401155. Epub 2008 Jan 11.


Phosphoinositides have crucial roles in cellular controls, many of which have been established through the use of small-molecule inhibitors. Here, we describe YM201636, a potent inhibitor of the mammalian class III phosphatidylinositol phosphate kinase PIKfyve, which synthesizes phosphatidylinositol 3,5-bisphosphate. Acute treatment of cells with YM201636 shows that the PIKfyve pathway is involved in the sorting of endosomal transport, with inhibition leading to the accumulation of a late endosomal compartment and blockade of retroviral exit. Inhibitor specificity is shown by the use of short interfering RNA against the target, as well as by rescue with the drug-resistant yeast orthologue Fab1. We concluded that the phosphatidylinositol 3,5-bisphosphate pathway is integral to endosome formation, determining morphology and cargo flux.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Animals
  • Biological Transport / drug effects
  • Biomarkers / metabolism
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism*
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • NIH 3T3 Cells
  • Phosphatidylinositol Phosphates / biosynthesis*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Retroviridae / drug effects*
  • Retroviridae / metabolism*


  • 6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide
  • Aminopyridines
  • Biomarkers
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,5-diphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase