A novel class of small molecule inhibitors of Hsp90.
A novel class of small molecule inhibitors of Hsp90.
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DOI：
10.1021/cb800162x
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发表时间：
2008-10-17
影响因子：
4
通讯作者：
Regan, Lynne
中科院分区：
文献类型：
--
作者：
Yi, Fang;Regan, Lynne
由生长促进蛋白的突变或失调引起的不受调节的细胞增殖是癌症的根本原因。许多这样的生长促进蛋白表现出对伴侣热休克蛋白90（Hsp 90）的活性的增加的依赖性，以在细胞中正确折叠和成熟。因此，可以预见抑制Hsp 90将是开发抗癌剂的有效且广泛适用的策略。热休克蛋白90在多分子伴侣复合物中的功能由ATP的结合和水解驱动。通过用17-AAG（一种活性位点结合ATP类似物）抑制Hsp 90已经获得了令人鼓舞的结果。在这里，我们提出了一种不同的方法来抑制热休克蛋白90破坏其相互作用的cochaperone命名的热休克蛋白组织蛋白（HOP）的结果。我们已经使用了基于AlphaScreen技术的高通量体外筛选来鉴定抑制这种相互作用的化合物。此外，我们证明这些化合物在体内是有活性的。用这些化合物处理人乳腺癌细胞系BT474和SKBR 3降低了Hsp 90依赖性客户蛋白HER 2的水平，并伴随相关的细胞死亡。
Unregulated cellular proliferation, caused by mutation or dysregulation of growth-promoting proteins, is an underlying cause of cancer. Many such growth-promoting proteins exhibit an increased dependence on the activity of the chaperone heat-shock protein 90 (Hsp90) for correct folding and maturation in the cell. One can therefore envision that inhibition of Hsp90 would be an effective and broadly applicable strategy for the development of anticancer agents. Hsp90 functions in multichaperone complexes driven by the binding and hydrolysis of ATP. Encouraging results have been obtained by inhibiting Hsp90 with 17-AAG, an active-site binding ATP analog. Here we present the results of a different approach to inhibiting Hsp90 by disrupting its interaction with a cochaperone named Hsp organizing protein (HOP). We have used an AlphaScreen technology based high-throughput in vitro screen to identify compounds that inhibit this interaction. In addition, we demonstrate that these compounds are active in vivo. Treatment of human breast cancer cell lines BT474 and SKBR3 with these compounds decreases the levels of the Hsp90-dependent client protein HER2, with associated cell death.
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DOI：
10.1073/pnas.91.18.8324
发表时间：
1994-08-30
影响因子：
11.1
作者：
WHITESELL, L;MIMNAUGH, EG;NECKERS, LM
通讯作者：
NECKERS, LM
影响因子：
50.5
作者：
Domingo-Domenech, J.;Fernandez, P. L.;Mellado, B.
通讯作者：
Mellado, B.
影响因子：
11.5
作者：
Ramanathan, Ramesh K.;Egorin, Merrill J.;Belani, Chandra P.
通讯作者：
Belani, Chandra P.
影响因子：
50.5
作者：
Cooke, T;Reeves, J;Stanton, P
通讯作者：
Stanton, P
影响因子：
4.8
作者：
Stankiewicz, AR;Lachapelle, G;Mosser, DD
通讯作者：
Mosser, DD