High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds

Acta Pharmacol Sin. 2018 Nov;39(11):1816-1822. doi: 10.1038/s41401-018-0057-z. Epub 2018 Jul 10.


The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.

Keywords: PI3 kinase; PI3Kα H1047R; high throughput screening; inhibitors; molecular modeling..

MeSH terms

  • High-Throughput Screening Assays
  • Humans
  • Hydrogen Bonding
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Molecular Docking Simulation
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism


  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors