Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform

Bioorg Med Chem Lett. 2013 May 1;23(9):2606-13. doi: 10.1016/j.bmcl.2013.02.102. Epub 2013 Mar 7.

Abstract

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.

MeSH terms

  • Benzoxepins / chemical synthesis
  • Benzoxepins / chemistry*
  • Benzoxepins / pharmacology
  • Binding Sites
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry*

Substances

  • Benzoxepins
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Thiazoles
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt