Design of selective PI3Kδ inhibitors using an iterative scaffold-hopping workflow

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2575-2580. doi: 10.1016/j.bmcl.2019.08.004. Epub 2019 Aug 5.


PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.

Keywords: Oxindole; PI3Kδ; Scaffold-hopping; Structure-based drug design.

MeSH terms

  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Structure
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry
  • Oxindoles / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
  • Phosphoinositide-3 Kinase Inhibitors / chemistry
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Oxindoles
  • Phosphoinositide-3 Kinase Inhibitors