Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9- (quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1 H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer

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

Research output: Contribution to journalArticle

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Abstract

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 (EC50 = 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.

Original languageEnglish
Pages (from-to)7146-7155
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number19
DOIs
Publication statusPublished - 2010 Oct 14
Externally publishedYes

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Sirolimus
Neoplasms
TOR Serine-Threonine Kinases
Growth Inhibitors
Phosphatidylinositol 3-Kinases
Heterografts
Protein Kinases
Phosphotransferases
Phosphorylation
Cell Proliferation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9- (quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1 H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. / Liu, Qingsong; Chang, Jae Won; Wang, Jinhua; Kang, Seong A.; Thoreen, Carson C.; Markhard, Andrew; Hur, Wooyoung; Zhang, Jianming; Sim, Taebo; Sabatini, David M.; Gray, Nathanael S.

In: Journal of Medicinal Chemistry, Vol. 53, No. 19, 14.10.2010, p. 7146-7155.

Research output: Contribution to journalArticle

Liu, Qingsong ; Chang, Jae Won ; Wang, Jinhua ; Kang, Seong A. ; Thoreen, Carson C. ; Markhard, Andrew ; Hur, Wooyoung ; Zhang, Jianming ; Sim, Taebo ; Sabatini, David M. ; Gray, Nathanael S. / Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9- (quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1 H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 19. pp. 7146-7155.
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