Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors

Bioorg Med Chem Lett. 2020 Jan 1;30(1):126715. doi: 10.1016/j.bmcl.2019.126715. Epub 2019 Oct 18.


A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Keywords: PI3Kδ inhibitor; Parallel medicinal chemistry; Phosphoinositide 3-kinase δ; Physicochemical properties; Structure-activity relationship.

MeSH terms

  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • High-Throughput Screening Assays / methods*
  • Humans
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Structure-Activity Relationship


  • Piperazines
  • Protein Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases