title: Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β.
abstract: Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Kendrick H
authors.initials: KH
authors.lastname: Yim
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Prince
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Shiwei
authors.initials: S
authors.lastname: Qu
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005;
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; Department of Physics and Astronomy, Rice University, Houston, TX 77005; Department of Chemistry, Rice University, Houston, TX 77005; Department of Biosciences, Rice University, Houston, TX 77005.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; neckersl@mail.nih.gov.
authors.forename: Leonard
authors.initials: L
authors.lastname: Neckers
mesh_terms: D003198:Computer Simulation; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D000072417:Protein Domains; D020033:Protein Isoforms; D044004:Xanthones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D020033:Protein Isoforms; D044004:Xanthones; C052659:gambogic acid
keywords: caged xanthone; heat-shock protein 90; isoform-specific inhibitor; molecular chaperone; molecular docking