Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo
文献类型：期刊论文
| 作者 | Xie, Hua2,3 ; Lee, Mee-Hyun2; Zhu, Feng2; Reddy, Kanamata2; Huang, Zunnan2; Kim, Dong Joon2; Li, Yan2; Peng, Cong2; Lim, Do Young2; Kang, Soouk2
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| 刊名 | MOLECULAR CANCER THERAPEUTICS
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| 出版日期 | 2013-06 |
| 卷号 | 12期号:6页码:950-958 |
| ISSN号 | 1535-7163 |
| DOI | 10.1158/1535-7163.MCT-12-1241 |
| 文献子类 | Article |
| 英文摘要 | The phosphoinositide 3-kinase (PI3-K)/Akt andmTORsignaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated inmanytypes of cancer. ThemTORkinase protein, one of the key molecules in this pathway, has been shown to be an important target for cancer therapy. In the present study, a ligand docking method was used to screen for novel scaffold mTOR inhibitors. Sixty thousand compounds in the Natural Product Database were screened against the mTOR homologous structure, and 13 commercially available compounds listed in the top-ranked 100 compounds were selected for further examination. Compound [(E)-3-(4-(benzo[d][1,3] dioxol-5-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one; designated herein as 3HOI-BA-01] was then selected for further study of its antitumor activity. An in vitro study has shown that 3HOI-BA-01 inhibited mTOR kinase activity in a dose-dependent manner by directly binding with mTOR. In a panel of non-small cell lung cancer cells, the compound also attenuated mTOR downstream signaling, including the phosphorylation of p70S6K, S6, and Akt, resulting in G(1) cell-cycle arrest and growth inhibition. Results of an in vivo study have shown that intraperitoneal injection of 3HOI-BA-01 in A549 lung tumor-bearing mice effectively suppressed cancer growth without affecting the body weight of the mice. The expression of downstream signaling molecules in the mTOR pathway in tumor tissues was also reduced after 3HOI-BA-01 treatment. Taken together, we identified 3HOI-BA-01 as a novel and effective mTOR inhibitor. (C) 2013 AACR. |
| WOS关键词 | MAMMALIAN TARGET ; CELL-GROWTH ; PATHWAY ; COMPLEX ; CANCER ; SENSITIVITY ; MECHANISMS ; KINASES ; AKT/PKB ; PI(3)K |
| 资助项目 | Hormel Foundation[00000000] ; NIH[CA120388] ; NIH[R37 CA081064] ; NIH[ES016548] ; NCI[HHSN261200533001 (N01-CN53301)] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000320110500011 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277599]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Dong, Zigang |
| 作者单位 | 1.NCI, NIH, Bethesda, MD 20892 USA; 2.Univ Minnesota, Hormel Inst, Austin, MN 55912 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Hua,Lee, Mee-Hyun,Zhu, Feng,et al. Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo[J]. MOLECULAR CANCER THERAPEUTICS,2013,12(6):950-958. |
| APA | Xie, Hua.,Lee, Mee-Hyun.,Zhu, Feng.,Reddy, Kanamata.,Huang, Zunnan.,...&Dong, Zigang.(2013).Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo.MOLECULAR CANCER THERAPEUTICS,12(6),950-958. |
| MLA | Xie, Hua,et al."Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo".MOLECULAR CANCER THERAPEUTICS 12.6(2013):950-958. |
入库方式： OAI收割
来源：上海药物研究所
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