EC144 Is a Potent Inhibitor of the Heat Shock Protein 90

被引：55

作者：

Shi, Jiandong ^{[1
]}

Van de Water, Ryan ^{[1
]}

Hong, Kevin ^{[1
]}

Lamer, Ryan B. ^{[1
]}

Weichert, Kenneth W. ^{[1
]}

Sandoval, Cristina M. ^{[1
]}

Kasibhatla, Srinivas R. ^{[1
]}

Boehm, Marcus F. ^{[1
]}

Chao, Jianhua ^{[1
]}

Lundgren, Karen ^{[1
]}

Timple, Noelito ^{[1
]}

Lough, Rachel ^{[1
]}

Ibanez, Gerardo ^{[1
]}

Boykin, Christina ^{[1
]}

Burrows, Francis J. ^{[1
]}

Kehry, Marilyn R. ^{[1
]}

Yun, Theodore J. ^{[1
]}

Harning, Erin K. ^{[1
]}

Ambrose, Christine ^{[2
]}

Thompson, Jeffrey ^{[2
]}

Bixler, Sarah A. ^{[2
]}

Dunah, Anthone ^{[2
]}

Snodgrass-Belt, Pamela ^{[2
]}

Arndt, Joseph ^{[2
]}

Enyedy, Istvan J. ^{[2
]}

Li, Ping ^{[2
]}

Hong, Victor S. ^{[2
]}

McKenzie, Andres ^{[2
]}

Biamonte, Marco A. ^{[1
]}

机构：

[1] Biogen Idec Inc, San Diego, CA 92122 USA

[2] Biogen Idec Inc, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 17期

关键词：

HSP90; INHIBITOR; BREAST-CANCER; ANTITUMOR ACTIVITIES; EXHIBITS POTENT; MYELOMA; DESIGN; HEAT-SHOCK-PROTEIN-90; TANESPIMYCIN; DERIVATIVES; MECHANISM;

D O I：

10.1021/jm300810x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90 alpha binding assay (IC50 = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC50 = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qdx5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.

引用

收藏

页码：7786 / 7795

页数：10

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