Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor

J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p.

Abstract

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Area Under Curve
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Nude
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics
  • Morpholines / pharmacology
  • Mutation
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / prevention & control
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Survival Analysis
  • TOR Serine-Threonine Kinases
  • Triazines / chemistry
  • Triazines / pharmacokinetics
  • Triazines / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Triazines
  • Adenosine Triphosphate
  • gedatolisib
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases