Structure-activity relationship study, target identification, and pharmacological characterization of a small molecular IL-12/23 inhibitor, APY0201

Bioorg Med Chem. 2014 Jun 1;22(11):3021-9. doi: 10.1016/j.bmc.2014.03.036. Epub 2014 Apr 13.

Abstract

Interleukin-12 (IL-12) and IL-23 are proinflammatory cytokines and therapeutic targets for inflammatory and autoimmune diseases, including inflammatory bowel diseases, psoriasis, rheumatoid arthritis, and multiple sclerosis. We describe the discovery of APY0201, a unique small molecular IL-12/23 production inhibitor, from activated macrophages and monocytes, and demonstrate ameliorated inflammation in an experimental model of colitis. Through a chemical proteomics approach using a highly sensitive direct nanoflow LC-MS/MS system and bait compounds equipped with the FLAG epitope associated regulator of PIKfyve (ArPIKfyve) was detected. Further study identified its associated protein phosphoinositide kinase, FYVE finger-containing (PIKfyve), as the target protein of APY0201, which was characterized as a potent, highly selective, ATP-competitive PIKfyve inhibitor that interrupts the conversion of phosphatidylinositol 3-phosphate (PtdIns3P) to PtdIns(3,5)P2. These results elucidate the function of PIKfyve kinase in the IL-12/23 production pathway and in IL-12/23-driven inflammatory disease pathologies to provide a compelling rationale for targeting PIKfyve kinase in inflammatory and autoimmune diseases.

Keywords: APY0201; IL-12/23; PIKfyve; Target identification.

MeSH terms

  • Animals
  • Cell Line
  • Colitis / drug therapy
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Female
  • Humans
  • Inflammation / drug therapy
  • Interleukin-10 / deficiency
  • Interleukin-12 / antagonists & inhibitors*
  • Interleukin-23 / antagonists & inhibitors*
  • Leukocytes, Mononuclear / drug effects
  • Macrophages / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • APY0201
  • Interleukin-23
  • Pyrazoles
  • Pyrimidines
  • Small Molecule Libraries
  • Interleukin-10
  • Interleukin-12