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.
Qingsong Liu  1 ,  Jinhua Wang ,  Seong A Kang ,  Carson C Thoreen ,  Wooyoung Hur ,  Tausif Ahmed ,  David M Sabatini ,  Nathanael S Gray
Affiliations
  • 1. Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, United States.
PMID: 21322566 DOI: 10.1021/jm101520v
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.

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