Preparation and optimization of new 4-(2-(indolin-1-yl)-2-oxoethyl)-2-morpholinothiazole-5-carboxylic acid and amide derivatives as potent and selective PI3Kβ inhibitors

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1506-10. doi: 10.1016/j.bmcl.2014.02.004. Epub 2014 Feb 8.

Abstract

In our continuous efforts to identify and develop novel targeted cancer treatments, a new morpholino-thiazole scaffold active against PI3Kβ has been identified. This Letter reports the optimization of this compound class to develop PI3Kβ isoform-selective inhibitors with suitable pharmacological properties.

Keywords: PI3Kβ; PTEN; Thiazole; pAKT.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Animals
  • Binding Sites
  • Caco-2 Cells
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Humans
  • Indoles / chemistry*
  • Male
  • Molecular Docking Simulation
  • Permeability / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thiazoles / chemistry

Substances

  • Amides
  • Carboxylic Acids
  • Indoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Thiazoles
  • indoline
  • Proto-Oncogene Proteins c-akt