title: 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.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Peng
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.forename: Soouk
authors.initials: S
authors.lastname: Kang
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000008:administration & dosage*; D063646:Carcinogenesis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D052117:Benzodioxoles; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C586450:3-(4-(benzo(d)(1,3)dioxol-5-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one; C546842:MTOR protein, human
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