Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2408-11. doi: 10.1016/j.bmcl.2010.03.046. Epub 2010 Mar 12.

Abstract

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.

MeSH terms

  • Animals
  • Dogs
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Mice
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • TOR Serine-Threonine Kinases
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Enzyme Inhibitors
  • GNE 477
  • Intracellular Signaling Peptides and Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Thiophenes
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases