title: Dimeric ansamycins--a new class of antitumor Hsp90 modulators with prolonged inhibitory activity.
abstract: The geldanamycin derivative 17-allyamino-17-demethoxygeldanamycin (17-AAG) is a clinical stage ATP-competitive HSP90 inhibitor that induces degradation of HSP90 client proteins. 17-AAG contains 1 ansamycin moiety and is highly potent in conventional cell killing assays. Since active Hsp90 exists as a dimer, we hypothesized that dimeric compounds containing 2 ansamycin pharmacophores might inhibit Hsp90 function more efficiently than 17-AAG. Here, we show that monomeric and dimeric ansamycins exert their activity in distinct ways. Under conditions of continuous exposure, 17-AAG induced client degradation and cell growth inhibition more readily than the dimeric drugs CF237 and CF483. By contrast, 24 hr treatment of various tumor cells with 17-AAG followed by drug washout caused temporary client degradation and cell cycle arrest but minimal cell death, whereas both dimers induced massive apoptosis. CF237 remained bound to Hsp90 for days after drug withdrawal and, while both monomeric and dimeric compounds caused accumulation of the inactive intermediate Hsp90 complex, this effect disappeared following washout of 17-AAG but not CF237. The dimer was also retained for longer in tumor xenografts and displayed superior antitumor activity in vivo. These results indicate that monomeric and dimeric Hsp90 inhibitors have distinct biological profiles and work differentially toward target inhibition.
authors.affiliation: Conforma Therapeutics Corporation, San Diego, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Yong-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: Daun
authors.initials: D
authors.lastname: Chung
authors.forename: Diana
authors.initials: D
authors.lastname: Choi
authors.forename: Roy
authors.initials: R
authors.lastname: Grecko
authors.forename: Gregg
authors.initials: G
authors.lastname: Timony
authors.forename: Patricia
authors.initials: P
authors.lastname: Karjian
authors.forename: Marcus
authors.initials: M
authors.lastname: Boehm
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016227:Benzoquinones / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D017828:Rifabutin; C502977:EC5 compound; C112765:tanespimycin