Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
J Med Chem. 2010 Oct 14;53(19):7146-55. doi: 10.1021/jm101144f.
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.
mTOR 蛋白是细胞生长和增殖的主要调节因子，其激酶活性抑制剂有可能成为新一类的抗癌药物。从在生化 mTOR 测定中鉴定出的喹啉 1 出发，我们开发了三环苯并萘啶酮抑制剂 37（Torin1），它在 2 和 10 nM 浓度下分别抑制细胞中 mTORC1 和 mTORC2 底物的磷酸化。此外，Torin1 对 mTOR 的选择性比 PI3K 高 1000 倍（EC(50) = 1800 nM），相对于其他 450 种蛋白激酶的结合选择性高 100 倍。Torin1 在 U87MG 异种移植模型中的剂量为 20 mg/kg 时有效，并在肿瘤和外周组织中显示出对 mTOR 下游效应物的良好药效抑制。这些结果表明 Torin1 是研究 mTOR 依赖性现象的有用探针，并且苯并萘啶酮代表了进一步开发具有临床应用潜力的 mTOR 特异性抑制剂的有前途的支架。
