Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer

J Med Chem. 2011 Mar 10;54(5):1473-80. doi: 10.1021/jm101520v. Epub 2011 Feb 15.

Abstract

The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(50): 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Drug Stability
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / pharmacokinetics
  • Naphthyridines / pharmacology
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Aminopyridines
  • Antineoplastic Agents
  • Naphthyridines
  • TOR Serine-Threonine Kinases