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首页> 外文期刊>Molecular cancer therapeutics >A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein
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A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein

机译：结合和抑制ETV1转录因子癌蛋白的小分子

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摘要

Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed "undruggable" by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins. (C) 2014 AACR.
机译：ETS转录因子家族的成员与多种癌症有关，在这些癌症中，它们常常因基因组失调而失调。 ETS变体1（ETV1）是一种ETS因子基因，在前列腺癌和尤因肉瘤中发生染色体易位，在黑色素瘤中扩增，在胃肠道间质瘤中发生谱系失调。在这些癌症中，ETV1的药理扰动将很有吸引力。然而，致癌转录因子通常被常规方法视为“不可吸收的”。在这里，我们使用小分子微阵列屏幕来识别和表征可调节ETV1生物学功能的类药物化合物。我们确定了1,3,5-三嗪小分子BRD32048为最佳候选ETV1微扰蛋白。 BRD32048直接绑定ETV1，调节ETV1介导的转录活性和ETV1驱动的癌细胞的侵袭。此外，BRD32048抑制ETV1的p300依赖性乙酰化，从而促进其降解。这些结果为药理性ETV1抑制开辟了一条新途径，并可能为发现转录因子癌蛋白小分子微扰的一般手段提供信息。 （C）2014 AACR。

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