Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5445-50. doi: 10.1016/j.bmcl.2012.07.042. Epub 2012 Jul 17.

Abstract

Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.

MeSH terms

  • Animals
  • Catalytic Domain
  • Female
  • Humans
  • Mice
  • Models, Molecular
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Signal Transduction / drug effects
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Thiazoles
  • 2-aminothiazole