Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors

Bioorg Med Chem Lett. 2017 Jul 1;27(13):3030-3035. doi: 10.1016/j.bmcl.2017.05.028. Epub 2017 May 10.

Abstract

We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kβ and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.

Keywords: Kinase selectivity; PI3Kα inhibitor; Rational design.

MeSH terms

  • Class I Phosphatidylinositol 3-Kinases
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human