Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: synthesis, biological evaluation and molecular modelling

Bioorg Med Chem. 2015 Jul 1;23(13):3796-808. doi: 10.1016/j.bmc.2015.03.073. Epub 2015 Apr 4.


A novel series of TGX-221 analogues was prepared and tested for their potency against the p110α, p110β, and p110δ isoforms of the PI3K enzyme, and in two cellular assays. The biological results were interpreted in terms of a p110β comparative model, in order to account for their selectivity towards this isoform. A CH2NH type linker is proposed to allow binding into the specificity pocket proposed to accommodate the high p110β-selectivity of TGX-221, although there was limited steric tolerance for substituents on the pendant ring with the 2-position most favourable for substitution.

Keywords: Comparative modelling; Docking; PI3K; Phosphatidylinositol 3-kinase; TGX-221; p110β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Class Ia Phosphatidylinositol 3-Kinase / chemistry
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Morpholines / chemical synthesis
  • Morpholines / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Subunits / antagonists & inhibitors*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Protein Subunits
  • Pyrimidinones
  • TGX 221
  • Class Ia Phosphatidylinositol 3-Kinase