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    ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A

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    Name:
    BMCL_REVISIONS_SM.pdf
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    Description:
    Final Accepted Manuscript
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    Author
    Tillotson, Joseph
    Kedzior, Magdalena
    Guimarães, Larissa
    Ross, Alison B.
    Peters, Tara L.
    Ambrose, Andrew J.
    Schmidlin, Cody J.
    Zhang, Donna D.
    Costa-Lotufo, Letícia V.
    Rodríguez, Abimael D.
    Schatz, Jonathan H.
    Chapman, Eli
    Show allShow less
    Affiliation
    Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol
    Issue Date
    2017-09-01
    Keywords
    Cancer
    Translation
    eIF4A
    Natural products
    DEAD box helicase
    Inhibitor
    
    Metadata
    Show full item record
    Publisher
    PERGAMON-ELSEVIER SCIENCE LTD
    Citation
    Tillotson, J., Kedzior, M., Guimarães, L., Ross, A. B., Peters, T. L., Ambrose, A. J., ... & Schatz, J. H. (2017). ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. Bioorganic & medicinal chemistry letters, 27(17), 4082-4085.
    Journal
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
    Rights
    © 2017 Elsevier Ltd. All rights reserved
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low mu M inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity. (C) 2017 Elsevier Ltd. All rights reserved.
    Note
    24 month embargo; available online 19 July 2017.
    ISSN
    0960894X
    DOI
    10.1016/j.bmcl.2017.07.045
    Version
    Final accepted manuscript
    Sponsors
    University of Arizona; National Institutes of Health (NIH) Training Grant [T32 GM008804, T32 HL007249]; National Institute of Environmental Health Sciences Training Grant [T32 ES007091]
    Additional Links
    https://linkinghub.elsevier.com/retrieve/pii/S0960894X17307412
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bmcl.2017.07.045
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