title: Gambogic acid, a natural product inhibitor of Hsp90.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, 246 Noble Research Center, Oklahoma State University, Stillwater, Oklahoma 74078, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Davenport
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Manjarrez
authors.forename: Laura
authors.initials: L
authors.lastname: Peterson
authors.forename: Brian
authors.initials: B
authors.lastname: Krumm
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Robert L
authors.initials: RL
authors.lastname: Matts
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D001688:Biological Products / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D018833:Chaperonins / Q000378:metabolism; D018360:Crystallography, X-Ray; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D011487:Protein Conformation; D013237:Stereoisomerism; D014315:Triterpenes / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D016227:Benzoquinones; D001688:Biological Products; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D044004:Xanthones; C052659:gambogic acid; D018833:Chaperonins; C050414:celastrol; C001277:geldanamycin