Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation

Chem Commun (Camb). 2014 May 25;50(40):5388-90. doi: 10.1039/c3cc48391f. Epub 2013 Dec 24.

Abstract

Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the β-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the β-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
  • Cell Proliferation / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Inositol Phosphates / antagonists & inhibitors*
  • Inositol Phosphates / metabolism
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Inositol Phosphates
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositol Phosphates
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • phosphatidylinositol 4-phosphate
  • inositol 1-phosphate
  • 1-Phosphatidylinositol 4-Kinase