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    Novobiocin Analogs That Inhibit the MAPK Pathway

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    Hall_2016.pdf (775.4Kb)
    Issue Date
    2016-02-11
    Author
    Hall, Jessica Ann
    Seedarala, Sahithi
    Zhao, Huiping
    Garg, Gaurav
    Ghosh, Suman
    Blagg, Brian S. J.
    Publisher
    American Chemical Society
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    Heat shock protein 90 (Hsp90) inhibition by modulation of the N-or C-terminal binding site has become an attractive strategy for the development of anti-cancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ~700 μM. Therefore, investigation of the novobiocin scaffold has led to analogs with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogs that do not inhibit Hsp90 were identified; however, these analogs demonstrated potent anti-proliferative activity. Compound 2, a novobiocin analog, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anti-cancer agents.
    Description
    This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/acs.jmedchem.5b01354.
    URI
    http://hdl.handle.net/1808/24384
    DOI
    https://doi.org/10.1021/acs.jmedchem.5b01354
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Hall, J. A., Seedarala, S., Zhao, H., Garg, G., Ghosh, S., & Blagg, B. S. J. (2016). Novobiocin Analogs That Inhibit the MAPK Pathway. Journal of Medicinal Chemistry, 59(3), 925–933. http://doi.org/10.1021/acs.jmedchem.5b01354

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    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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