Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors

Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21.

Abstract

We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Triazines / chemistry
  • Triazines / metabolism
  • Triazines / pharmacology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Triazines
  • TOR Serine-Threonine Kinases