Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα)

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3189-93. doi: 10.1016/j.bmcl.2015.05.093. Epub 2015 Jun 4.

Abstract

The discovery and optimisation of novel, potent and selective small molecule inhibitors of the α-isoform of type III phosphatidylinositol-4-kinase (PI4Kα) are described. Lead compounds show cellular activity consistent with their PI4Kα potency inhibiting the accumulation of IP1 after PDGF stimulation and reducing cellular PIP, PIP2 and PIP3 levels. Hence, these compounds are useful in vitro tools to delineate the complex biological pathways involved in signalling through PI4Kα.

Keywords: IP1; In vitro tools; Oncology; PI4Kα.

MeSH terms

  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Inositol Phosphates / metabolism
  • Minor Histocompatibility Antigens
  • Models, Molecular
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Platelet-Derived Growth Factor / pharmacology
  • Signal Transduction / drug effects
  • Small Molecule Libraries
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Inositol Phosphates
  • Minor Histocompatibility Antigens
  • Platelet-Derived Growth Factor
  • Small Molecule Libraries
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase