A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.
A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.
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DOI：
10.1158/1535-7163.mct-13-0689
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发表时间：
2014-06
影响因子：
5.7
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Pop MS;Stransky N;Garvie CW;Theurillat JP;Hartman EC;Lewis TA;Zhong C;Culyba EK;Lin F;Daniels DS;Pagliarini R;Ronco L;Koehler AN;Garraway LA
ETS转录因子家族的成员与几种癌症有关，在这些癌症中，它们通常因基因组紊乱而失调。ETS变体1（ETV 1）是一种ETS因子基因，在前列腺癌和尤文氏肉瘤中发生染色体易位，在黑色素瘤中发生扩增，在胃肠道间质瘤中发生谱系失调。ETV 1的药理学干扰在这些癌症中是有吸引力的;然而，致癌转录因子通常被常规方法认为是“不可治疗的”。在这里，我们使用小分子微阵列（SMM）筛选来鉴定和表征调节ETV 1生物学功能的药物样化合物。我们鉴定了1，3，5-三嗪小分子BRD 32048作为最佳候选ETV 1干扰剂。BRD 32048直接结合ETV 1，调节ETV 1介导的转录活性和ETV 1驱动的癌细胞的侵袭。此外，BRD 32048抑制ETV 1的p300依赖性乙酰化，从而促进其降解。这些结果指出了一个新的途径，药理学ETV 1抑制，并可能通知一个通用的手段来发现转录因子癌蛋白的小分子扰动。
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's 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 (SMM) screens to identify and characterize drug-like compounds that modulate the biological 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 pharmacological ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.