Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90

被引：160

作者：

Ge, Jie ^{[1
]}

Normant, Emmanuel ^{[1
]}

Porter, James R. ^{[1
]}

Ali, Janid A. ^{[1
]}

Dembski, Marlene S. ^{[1
]}

Gao, Yun ^{[1
]}

Georges, Asimina T. ^{[1
]}

Grenier, Louis ^{[1
]}

Pak, Roger H. ^{[1
]}

Patterson, Jon ^{[1
]}

Sydor, Jens R. ^{[1
]}

Tibbitts, Thomas T. ^{[1
]}

Tong, Jeffrey K. ^{[1
]}

Adams, Julian ^{[1
]}

Palombella, Vito J. ^{[1
]}

机构：

[1] Infin Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 15期

关键词：

HEAT-SHOCK-PROTEIN; N-TERMINAL DOMAIN; MOLECULAR CHAPERONE; GELDANAMYCIN DERIVATIVES; CRYSTAL-STRUCTURE; GROWTH ARREST; HEAT-SHOCK-PROTEIN-90; CANCER; EXPRESSION; DEGRADATION;

D O I：

10.1021/jm0603116

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

17-Allylamino-17-demethoxygeldanamycin (17-AAG)(1) is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

引用

页码：4606 / 4615

页数：10

共 66 条

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