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
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
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1-( 4-( 4-丙酰哌嗪-1-基 )-3-( 三氟甲基 ) 苯基 )-9-( 喹啉-3-基 ) 苯并 [ h ] [ 1 , 6 ] naphthyridin-2 ( 1 H ) 的发现
DOI：
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
N. Gray
中科院分区：
文献类型：
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作者：
Qingsong Liu;J. Chang;Jun Wang;S. A. Kang;Catie Carson;Thoreen;Andrew L. Markhard;W. Hur;Jianming Zhang;Taebo Sim;David A. Mortensen;M. H. Sabatini;N. Gray
mTOR蛋白是细胞生长和增殖的主要调节剂，其激酶活性的抑制剂有可能成为新一类抗癌药物。从在生化mTOR试验中鉴定的喹啉1开始，我们开发了三环苯并萘啶酮抑制剂Torin 1（26），其分别在2 nM和10 nM浓度下抑制细胞中mTORC 1和mTORC 2底物的磷酸化。此外，Torin 1对mTOR的选择性是PI 3 K的1000倍（EC 50 = 1800 nM），对其他450种蛋白激酶的结合选择性是100倍。Torin 1在U87 MG异种移植模型中以20 mg/ kg的剂量有效，并表现出对肿瘤和外周组织中mTOR下游效应物的良好药效学抑制。这些结果表明，Torin 1是一个有用的探针的mTOR依赖性的现象，苯并萘啶酮代表了一个有前途的支架mTOR特异性抑制剂的进一步发展，具有潜在的临床效用。
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 anti-cancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor Torin1(26), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 nM 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.
DOI：
10.1073/pnas.95.25.14950
发表时间：
1998-12-08
影响因子：
11.1
作者：
Aoki, M;Batista, O;Vogt, PK
通讯作者：
Vogt, PK
影响因子：
16
作者：
Yip CK;Murata K;Walz T;Sabatini DM;Kang SA
通讯作者：
Kang SA
影响因子：
16
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
通讯作者：
Sabatini, DM