Design, Synthesis, and Biological Evaluation of Hydroquinone Derivatives of 17-Amino-17-demethoxygeldanamycin as Potent, Water-Soluble Inhibitors of Hsp90
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- 作者：Jie Ge ; Emmanuel Normant ; James R. Porter ; Janid A. Ali ; Marlene S. Dembski ; Yun Gao ; Asimina T. Georges ; Louis Grenier ; Roger H. Pak ; Jon Patterson ; Jens R. Sydor ; Thomas T. Tibbitts ; Jeffrey K. Tong
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：July 27, 2006
- 年：2006
- 卷：49
- 期：15
- 页码：4606 - 4615
- 全文大小：191K
- 年卷期：v.49,no.15(July 27, 2006)
- ISSN：1520-4804
文摘
17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shockprotein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challengingformulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly solublehydroquinone 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 growthof the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, andcause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is aclear correlation between the measured binding affinity of the compounds and their cellular activities. Uponthe basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currentlyunder evaluation in Phase I clinical trials for cancer.