Synthesis and evaluation of pyrrolotriazine based molecules as PI3 kinase inhibitors

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3142-6. doi: 10.1016/j.bmcl.2015.06.007. Epub 2015 Jun 10.

Abstract

Over activation of the PI3K/Akt/mTOR pathway is found in most cancer tumor types. Controlled regulation of this pathway using PI3K inhibitors can provide therapeutic significance in cancer treatment. Herein, we report the synthesis and evaluation of pyrrolotriazine based novel small molecules as pan-PI3K inhibitors. The SAR studies based on in vitro potency along with microsomal metabolic stability screening, identified 18 as a preclinical lead found to be suitable for in vivo evaluation. The identified lead was also found to be a selective inhibitor of PI3K isoforms and mTOR when screened across a panel of 23 homologous kinases.

Keywords: Kinase screening; Oncology; PI3K inhibitor; PI3K/Akt/mTOR pathway; Pyrrolotriazine.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Humans
  • Microsomes / metabolism
  • Molecular Docking Simulation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Triazines / chemistry*
  • Triazines / metabolism
  • Triazines / pharmacology

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Triazines
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases