PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling

Chem Biol. 2013 Jul 25;20(7):912-21. doi: 10.1016/j.chembiol.2013.05.010.


Toll-like receptor (TLR) signaling is a key component of innate immunity. Aberrant TLR activation leads to immune disorders via dysregulation of cytokine production, such as IL-12/IL-23. Herein, we identify and characterize PIKfyve, a lipid kinase, as a critical player in TLR signaling using apilimod as an affinity tool. Apilimod is a potent small molecular inhibitor of IL-12/IL-23 with an unknown target and has been evaluated in clinical trials for patients with Crohn's disease or rheumatoid arthritis. Using a chemical genetic approach, we show that it binds to PIKfyve and blocks its phosphotransferase activity, leading to selective inhibition of IL-12/IL-23p40. Pharmacological or genetic inactivation of PIKfyve is necessary and sufficient for suppression of IL-12/IL-23p40 expression. Thus, we have uncovered a phosphoinositide-mediated regulatory mechanism that controls TLR signaling.

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Hydrazones
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-23 / antagonists & inhibitors*
  • Mice
  • Morpholines / metabolism
  • Morpholines / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Pyrimidines
  • Signal Transduction / drug effects*
  • Substrate Specificity
  • Toll-Like Receptors / metabolism*
  • Triazines / metabolism
  • Triazines / pharmacology*


  • Cytokines
  • Enzyme Inhibitors
  • Hydrazones
  • Interleukin-23
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Toll-Like Receptors
  • Triazines
  • Interleukin-12
  • apilimod mesylate
  • PIKFYVE protein, human