Expanding the repertoire of small molecule transcriptional activation domains
Expanding the repertoire of small molecule transcriptional activation domains
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DOI：
10.1016/j.bmc.2008.02.045
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Mapp, Anna K.
中科院分区：
文献类型：
--
作者：
Casey, Ryan J.;Desaulniers, Jean-Paul;Mapp, Anna K.
能够重建转录激活因子功能的分子作为治疗剂和机制探针具有巨大的潜力。以前，我们描述了一个异恶唑烷轴承功能团类似于天然的转录激活因子，上调转录80倍，在1 μ M的细胞培养。在这项研究中，我们分析了这种分子的类似物，以确定在细胞中作为转录激活结构域的小分子的关键特征。构象刚性是一个重要的贡献功能是一个整体的两亲性取代模式。使用这些标准，我们确定了额外的分子支架具有优异的（类似于60倍）的活性作为转录激活结构域。这些结果为创造具有这种功能的新一代小分子指明了方向。(C)2008爱思唯尔有限公司保留所有权利。
Molecules that can reconstitute the function of transcriptional activators hold enormous potential as therapeutic agents and as mechanistic probes. Previously we described an isoxazolidine bearing functional groups similar to natural transcriptional activators that up-regulates transcription 80-fold at 1 mu M in cell culture. In this study, we analyze analogs of this molecule to define key characteristics of small molecules that function as transcriptional activation domains in cells. Conformational rigidity is an important contributor to function as is an overall amphipathic substitution pattern. Using these criteria, we identified additional molecular scaffolds with excellent (similar to 60-fold) activity as transcriptional activation domains. These results point the way for the creation of new generations of small molecules with this function. (C) 2008 Elsevier Ltd. All rights reserved.