Gambogic Acid, a Natural Product Inhibitor of Hsp90
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Issue Date
2011-04-12Author
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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Show full item recordAbstract
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.
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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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