Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins.
Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins.
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DOI：
10.1021/cb200203m
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发表时间：
2011-12-16
影响因子：
4
通讯作者：
McAlpine, Shelli R.
中科院分区：
文献类型：
--
作者：
Ardi, Veronica C.;Alexander, Leslie D.;Johnson, Victoria A.;McAlpine, Shelli R.
热休克蛋白90(Hsp90)在正常细胞中占总蛋白的1-2%，是折叠、组装和稳定客户蛋白的分子伴侣。HSP90在包括癌细胞在内的应激细胞中过度表达(增加3-6倍)，并调节超过200个客户和辅助伴侣蛋白。HSP90客户蛋白参与了大量的细胞信号事件，包括大量的生长和凋亡途径。由于途径特异性抑制剂在耐药癌症中可能存在问题，因此在开发新的治疗方法时，同时关闭多个途径是一个很有前途的方法。热休克蛋白90的S能够同时调节许多生长和信号通路，使该蛋白成为癌症治疗领域的一个有吸引力的靶点。在这里，我们提供了证据，表明一个小分子通过N和中间结构域之间的结合以及变构抑制Hsp90与四个C末端结合客户蛋白之间的结合作用来调节Hsp90：IP6K2、FKBP38、FKBP52和HOP。这最后三个客户端包含一个四肽重复(TPR)区域，已知该区域与Hsp90 C-末端的MEEVD序列相互作用。因此，这个小分子调控含有TPR基序的辅助伴侣和Hsp90‘S MEEVD区域之间的活性。这种作用机制与目前正在进行临床试验的所有Hsp90抑制剂不同，在临床试验中，这些分子对与Hsp90 C末端结合的蛋白质没有影响。此外，我们的小分子诱导依赖于Caspase-3的凋亡事件。因此，我们描述了一种新型支架的机制，该支架是研究当阻断Hsp90和辅助伴侣蛋白之间的MEEVD-TPR相互作用时导致的细胞信号事件的有用工具。
Heat shock protein 90 (Hsp90) accounts for 1–2% of the total proteins in normal cells and functions as a molecular chaperone that folds, assembles, and stabilizes client proteins. Hsp90 is over-expressed (3–6-fold increase) in stressed cells, including cancer cells, and regulates over 200 client and co-chaperone proteins. Hsp90 client proteins are involved in a plethora of cellular signaling events including numerous growth and apoptotic pathways. Since pathway-specific inhibitors can be problematic in drug-resistant cancers, shutting down multiple pathways at once is a promising approach when developing new therapeutics. Hsp90’s ability to modulate many growth and signaling pathways simultaneously makes this protein an attractive target in the field of cancer therapeutics. Herein we present evidence that a small molecule modulates Hsp90 via binding between the N and middle domain and allosterically inhibiting the binding interaction between Hsp90 and four C-terminal binding client proteins: IP6K2, FKBP38, FKBP52, and HOP. These last three clients contain a tetratricopeptide-repeat (TPR) region, which is known to interact with the MEEVD sequence on the C-terminus of Hsp90. Thus, this small molecule modulates the activity between co-chaperones that contain TPR motifs and Hsp90’s MEEVD region. This mechanism of action is unique from that of all Hsp90 inhibitors currently in clinical trials where these molecules have no effect on proteins that bind to the C-terminus of Hsp90. Further, our small molecule induces a Caspase-3 dependent apoptotic event. Thus, we describe the mechanism of a novel scaffold that is a useful tool for studying cell-signaling events that result when blocking the MEEVD-TPR interaction between Hsp90 and co-chaperone proteins.
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影响因子：
2.7
作者：
Kunicki, Joseph B.;Petersen, Mark N.;Alexander, Leslie D.;Ardi, Veronica C.;McConnell, Jeanette R.;McAlpine, Shelli R.
通讯作者：
McAlpine, Shelli R.
影响因子：
45.3
作者：
Grem, JL;Morrison, G;Wilson, RH
通讯作者：
Wilson, RH
影响因子：
--
作者：
Jez, JM;Chen, JCH;Santi, DV
通讯作者：
Santi, DV
影响因子：
16.8
作者：
Hessling, Martin;Richter, Klaus;Buchner, Johannes
通讯作者：
Buchner, Johannes
DOI：
10.1073/pnas.0711168105
发表时间：
2008-01-29
影响因子：
11.1
作者：
Chakraborty, Anutosh;Koldobskiy, Michael A.;Snyder, Solomon H.
通讯作者：
Snyder, Solomon H.