Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a Highly Potent, Selective Mammalian Target of Rapamycin (mTOR) Inhibitor for the Treatment of Cancer

• DOI: 10.1021/jm101144f
• Publication Date: 2010-09-22T14:12:40Z
• Authors: Qingsong Liu; Jae Won Chang; Jinhua Wang; Seong A. Kang; Carson C. Thoreen; Andrew Markhard; Wooyoung Hur; Jianming Zhang; Taebo Sim; David M. Sabatini; Nathanael S. Gray
• Keywords: Male; Models, Molecular; 0303 health sciences; TOR Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Mice, Nude; Antineoplastic Agents; In Vitro Techniques; Protein Serine-Threonine Kinases; Xenograft Model Antitumor Assays; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Microsomes, Liver; Animals; Humans; Naphthyridines; Phosphorylation; Phosphoinositide-3 Kinase Inhibitors

The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anticancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor 37 (Torin1), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC(50) = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin1 was efficacious at a dose of 20 mg/kg in a U87MG xenograft model and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. These results demonstrate that Torin1 is a useful probe of mTOR-dependent phenomena and that benzonaphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clinical utility.