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Dimeric ansamycins—A new class of antitumor Hsp90 modulators with prolonged inhibitory activity
Author(s) -
Zhang Hong,
Yang YongChing,
Zhang Lin,
Fan Junhua,
Chung Daun,
Choi Diana,
Grecko Roy,
Timony Gregg,
Karjian Patricia,
Boehm Marcus,
Burrows Francis
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22392
Subject(s) - geldanamycin , hsp90 , hsp90 inhibitor , in vivo , dimer , chemistry , pharmacophore , biochemistry , moiety , cell cycle checkpoint , cell growth , cytotoxicity , apoptosis , in vitro , pharmacology , stereochemistry , cell cycle , biology , heat shock protein , microbiology and biotechnology , organic chemistry , gene
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. © 2006 Wiley‐Liss, Inc.