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Discovery of the novel mTOR inhibitor and its antitumor activities in vitro and in vivo.

ABSTRACT: The phosphoinositide 3-kinase (PI3-K)/Akt and mTOR signaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated in many types of cancer. The mTOR kinase 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 G1 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.

SUBMITTER: Xie H

PROVIDER: S-EPMC3681861 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Discovery of the novel mTOR inhibitor and its antitumor activities in vitro and in vivo.

Xie Hua H Lee Mee-Hyun MH Zhu Feng F Reddy Kanamata K Huang Zunnan Z Kim Dong Joon DJ Li Yan Y Peng Cong C Lim Do Young DY Kang Soouk S Jung Sung Keun SK Li Xiang X Li Haitao H Ma Weiya W Lubet Ronald A RA Ding Jian J Bode Ann M AM Dong Zigang Z

Molecular cancer therapeutics 20130327 6

The phosphoinositide 3-kinase (PI3-K)/Akt and mTOR signaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated in many types of cancer. The mTOR kinase 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 mTO ...[more]

PMID: 23536724

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Discovery of the novel mTOR inhibitor and its antitumor activities in vitro and in vivo.

Publications

Discovery of the novel mTOR inhibitor and its antitumor activities in vitro and in vivo.

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