4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2259-63. doi: 10.1016/j.bmcl.2010.02.012. Epub 2010 Feb 6.

Abstract

A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Benzofurans / chemistry*
  • Benzofurans / pharmacology*
  • Class Ib Phosphatidylinositol 3-Kinase
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Isoenzymes / chemistry
  • Models, Molecular
  • Phosphatidylinositol 3-Kinases / chemistry
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism*
  • Sirolimus
  • Structural Homology, Protein
  • TOR Serine-Threonine Kinases

Substances

  • Benzofurans
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • MTOR protein, human
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus