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. 2010 Oct 14;53(19):7146-55.
doi: 10.1021/jm101144f.

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

Qingsong Liu  1 , 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
Affiliations

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

Qingsong Liu et al. J Med Chem. .

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 (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.

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Figures

Figure 1
Figure 1
Chemical structures of reported ATP-competitive mTOR inhibitors
Figure 2
Figure 2
Screening flowchart for development of mTOR inhibitors
Figure 3
Figure 3
Model demonstration of compound 7 binding with mTOR
Figure 4
Figure 4
Representative structure of variations of R1
Figure 5
Figure 5
Representative structures of variations of R2
Figure 6
Figure 6
Pharmacodynamic inhibition of Akt S473 and S6 S235/236 phosphorylation in lung and liver of mice treated with a single intraperotineal dose of 20 mg/Kg 26.a
Figure 7
Figure 7
In vivo efficacy of 26 in U87MG xenografts.a aMice model was established with 6 week old immunodeficient mice by subcutaneous injection of U87MG cells. 26 as a solution /suspension in vehicle (20% N-mentyl-2-pyrrolidone, 40% PEG400 and 40% water) or vehicle was delivered by intraperitoneal injection once daily after the tumor reached 1 cm3 in size and continued for 10 days.
Scheme 1
Scheme 1
Reagents and conditions: 1. appropriate anline, 1,4-dioxane, 100 °C, 6h; 2. appropriate boronic acid, PdCl-2(Ph3P)2, t-Bu-Xphos, Na2CO3, Dioxane, 100 °C, 4h-12h.
Scheme 2
Scheme 2
Reagents and conditions: 1. aniline (R2NH2), 1,4-dioxane, 100 °C, 4h; 2. LAH, THF, 0°C-rt, 4h; 3. a) MnO2, CH2Cl2, rt, 6h, b) triethyl phosphonoacetate, K2CO3, EtOH, 100 °C, 12h; 4. R1B(OH)2, PdCl2(Ph3P)2, t-Bu-Xphos, Na2CO3, 1,4-dioxane, 100 °C, 12h
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References

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