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
作者： Qingsong Liu , Jinhua Wang , Seong A. Kang , Carson C. Thoreen , Wooyoung Hur
DOI: 10.1021/JM101520V
关键词:
摘要: The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in broad spectrum of cancers. Starting from the selective inhibitor 1 (Torin1), focused medicinal chemistry effort led discovery an improved 3 (Torin2), which possesses EC50 0.25 nM for inhibiting cellular activity. Compound exhibited 800-fold selectivity over PI3K (EC50: 200 nM) and 100-fold binding relative 440 other protein kinases. significantly bioavailability (54%), metabolic stability, plasma exposure compound 1.
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