Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

被引：183

作者：

Sydor, Jens R. ^{[1
]}

Normant, Emmanuel ^{[1
]}

Pien, Christine S. ^{[1
]}

Porter, James R. ^{[1
]}

Ge, Jie ^{[1
]}

Grenier, Louis ^{[1
]}

Pak, Roger H. ^{[1
]}

Ali, Janid A. ^{[1
]}

Dembski, Marlene S. ^{[1
]}

Hudak, Jebecka ^{[1
]}

Patterson, Jon ^{[1
]}

Penders, Courtney ^{[1
]}

Pink, Melissa ^{[1
]}

Read, Margaret A. ^{[1
]}

Sang, Jim ^{[1
]}

Woodward, Caroline ^{[1
]}

Zhang, Yilong ^{[1
]}

Grayzel, David S. ^{[1
]}

Wright, Jim ^{[1
]}

Barrett, John A. ^{[1
]}

Palombella, Vito J. ^{[1
]}

Adams, Julian ^{[1
]}

Tong, Jeffrey K. ^{[1
]}

机构：

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

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2006年 / 103卷 / 46期

关键词：

D O I：

10.1073/pnas.0608372103

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.

引用

页码：17408 / 17413

页数：6

共 38 条

[1] Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 - A novel basis for antileukemia activity of histone deacetylase inhibitors [J].