Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents

被引：174

作者：

Huang, Kenneth H. ^{[1
]}

Veal, James M. ^{[1
]}

Fadden, R. Patrick ^{[1
]}

Rice, John W. ^{[1
]}

Eaves, Jeron ^{[1
]}

Strachan, Jon-Paul ^{[1
]}

Barabasz, Amy F. ^{[1
]}

Foley, Briana E. ^{[1
]}

Barta, Thomas E. ^{[1
]}

Ma, Wei ^{[1
]}

Silinski, Melanie A. ^{[1
]}

Hu, Mei ^{[1
]}

Partridge, Jeffrey M. ^{[1
]}

Scott, Anisa ^{[1
]}

DuBois, Laura G. ^{[1
]}

Freed, Tiffany ^{[1
]}

Steed, Paul M. ^{[1
]}

Ommen, Andy J. ^{[1
]}

Smith, Emilie D. ^{[1
]}

Hughes, Philip F. ^{[1
]}

Woodward, Angela R. ^{[1
]}

Hanson, Gunnar J. ^{[1
]}

McCall, W. Stephen ^{[1
]}

Markworth, Christopher J. ^{[1
]}

Hinkley, Lindsay ^{[1
]}

Jenks, Matthew ^{[1
]}

Geng, Lifeng ^{[1
]}

Lewis, Meredith ^{[1
]}

Otto, James ^{[1
]}

Pronk, Bert ^{[1
]}

Verleysen, Katleen ^{[1
]}

Hall, Steven E. ^{[1
]}

机构：

[1] Serenex Inc, Durham, NC 27701 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 14期

关键词：

BIOLOGICAL EVALUATION; ATP BINDING; HSP90; HEAT-SHOCK-PROTEIN-90; CANCER; GELDANAMYCIN; HYDROQUINONE; DERIVATIVES; CHAPERONE; TARGET;

D O I：

10.1021/jm900230j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC50 Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.

引用

页码：4288 / 4305

页数：18

共 62 条

[11] Hsp90: the vulnerable chaperone [J].