Inhibition of HSP90 with Pochoximes: SAR and Structure-Based Insights

被引：40

作者：

Barluenga, Sofia ^{[1
]}

Fontaine, Jean-Gonzague ^{[1
]}

Wang, Cuihua ^{[1
]}

Aouadi, Kais ^{[1
]}

Chen, Ruihong ^{[2
]}

Beebe, Kristin ^{[3
]}

Neckers, Len ^{[3
]}

Winssinger, Nicolas ^{[1
]}

机构：

[1] Univ Strasbourg, Inst Sci & Ingenierie Supramol, CNRS, UMR7006, F-67000 Strasbourg, France

[2] Negenix Pharmaceut, New York, NY 10019 USA

[3] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA

来源：

CHEMBIOCHEM | 2009年 / 10卷 / 17期

关键词：

Hsp90; inhibitors; pochoxime; radicicol; structure-activity relationships; SHOCK-PROTEIN; 90; SMALL-MOLECULE INHIBITORS; N-TERMINAL DOMAIN; BIOLOGICAL EVALUATION; ANTITUMOR-ACTIVITY; IN-VIVO; HEAT-SHOCK-PROTEIN-90; INHIBITOR; ANTICANCER AGENT; CHAPERONE HSP90; TARGETING HSP90;

D O I：

10.1002/cbic.200900494

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure-activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins.

引用

页码：2753 / 2759

页数：7

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