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    Gambogic Acid, a Natural Product Inhibitor of Hsp90

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    Issue Date
    2011-04-12
    Author
    Davenport, Jason
    Manjarrez, Jacob R.
    Peterson, Laura B.
    Krumm, Brian
    Blagg, Brian S. J.
    Matts, Robert L.
    Publisher
    Journal of Natural Products
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Rights
    Copyright © 2011 The American Chemical Society and American Society of Pharmacognosy
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    Abstract
    A high-throughput screening of natural product libraries identified (−)-gambogic acid (1), a component of the exudate of Garcinia harburyi, as a potential Hsp90 inhibitor, in addition to the known Hsp90 inhibitor celastrol (2). Subsequent testing established that 1 inhibited cell proliferation, brought about the degradation of Hsp90 client proteins in cultured cells, and induced the expression of Hsp70 and Hsp90, which are hallmarks of Hsp90 inhibition. Gambogic acid also disrupted the interaction of Hsp90, Hsp70, and Cdc37 with the heme-regulated eIF2α kinase (HRI, an Hsp90-dependent client) and blocked the maturation of HRI in vitro. Surface plasmon resonance spectroscopy indicated that 1 bound to the N-terminal domain of Hsp90 with a low micromolar Kd, in a manner that was not competitive with the Hsp90 inhibitor geldanamycin (3). Molecular docking experiments supported the posit that 1 binds Hsp90 at a site distinct from Hsp90s ATP binding pocket. The data obtained have firmly established 1 as a novel Hsp90 inhibitor and have provided evidence of a new site that can be targeted for the development of improved Hsp90 inhibitors.
    URI
    http://hdl.handle.net/1808/22583
    DOI
    https://doi.org/10.1021/np200029q
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Davenport, Jason, Jacob R. Manjarrez, Laura Peterson, Brian Krumm, Brian S. J. Blagg, and Robert L. Matts. "Gambogic Acid, a Natural Product Inhibitor of Hsp90." Journal of Natural Products 74.5 (2011): 1085-092.

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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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