Discovery of inhibitors of aberrant gene transcription from Libraries of DNA binding molecules: inhibition of LEF-1-mediated gene transcription and oncogenic transformation.
Discovery of inhibitors of aberrant gene transcription from Libraries of DNA binding molecules: inhibition of LEF-1-mediated gene transcription and oncogenic transformation.
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从DNA结合分子库中发现异常基因转录的抑制剂：抑制LEF-1介导的基因转录和致癌转化。
DOI：
10.1021/ja809083d
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发表时间：
2009-03-11
影响因子：
15
通讯作者：
Boger DL
中科院分区：
文献类型：
--
作者：
Stover JS;Shi J;Jin W;Vogt PK;Boger DL
筛选> 9000个合成DNA结合分子的化合物文库以选择性结合转录因子LEF-1的共有序列，然后在一系列表征功能活性的测定中评估候选化合物（破坏DNA-LEF-1结合）（抑制细胞内LEF-1介导的基因转录）导致所需的表型细胞变化（抑制LEF-1驱动的细胞转化）提供了两种先导化合物：lefmycin-1和lefmycin-2。定义该方法的筛选顺序确保最终功能测定中的活性可能与所鉴定分子的基因转录抑制和DNA结合特性直接相关。实施这种发现DNA结合基因转录的小分子抑制剂的通用方法的核心是：（1）使用技术上要求不高的荧光嵌入剂置换（FID）测定来初步评估化合物文库对任何感兴趣序列的DNA结合亲和力和选择性，和（2）用于制备足够大的DNA结合化合物文库的技术。
The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity (disruption of DNA–LEF-1 binding) at the intended target and site (inhibition of intracellular LEF-1 mediated gene transcription) resulting in a desired phenotypic cellular change (inhibit LEF-1 driven cell transformation) provided two lead compounds: lefmycin-1 and lefmycin-2. The sequence of screens defining the approach assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules. Central to the implementation of this generalized approach to the discovery of DNA binding small molecule inhibitors of gene transcription was: (1) the use of a technically non-demanding fluorescent intercalator displacement (FID) assay for initial assessment of the DNA binding affinity and selectivity of a library of compounds for any sequence of interest, and (2) the technology used to prepare a sufficiently large library of DNA binding compounds.
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影响因子：
15
作者：
Cheng, S;Comer, DD;Boger, DL
通讯作者：
Boger, DL
影响因子：
15
作者：
Boger, DL;Fink, BE;Hedrick, MP
通讯作者：
Hedrick, MP
影响因子：
11.4
作者：
GIESE, K;GROSSCHEDL, R
通讯作者：
GROSSCHEDL, R
影响因子：
64.8
作者：
LOVE, JJ;LI, XA;WRIGHT, PE
通讯作者：
WRIGHT, PE
影响因子：
3.7
作者：
BISTER, K;HAYMAN, MJ;VOGT, PK
通讯作者：
VOGT, PK