BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells.
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells.
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DOI：
10.1186/s13395-017-0134-x
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发表时间：
2017-09-04
期刊：
影响因子：
4.9
通讯作者：
Sverdrup FM
中科院分区：
文献类型：
--
作者：
Campbell AE;Oliva J;Yates MP;Zhong JW;Shadle SC;Snider L;Singh N;Tai S;Hiramuki Y;Tawil R;van der Maarel SM;Tapscott SJ;Sverdrup FM
面肩肱营养不良 (FSHD) 是一种进行性肌肉疾病，由导致骨骼肌中双同源框 4 (DUX4) 基因表观遗传去抑制和不适当转录的突变引起。因此，增强 DUX4 抑制并阻止其在骨骼肌细胞中表达的药物代表了 FSHD 的候选疗法。我们筛选了一个富含具有表观遗传活性的化合物的聚合化学文库，以及由已达到临床测试的化合物组成的 Pharmakon 1600 文库，以识别降低 DUX4 表达的分子（通过 FSHD 患者来源的骨骼肌细胞培养物中 DUX4 靶基因的水平进行监测）。我们的筛选鉴定了几类分子，其中包括溴结构域和末端外 (BET) 蛋白家族的抑制剂以及 β2 肾上腺素能受体的激动剂。进一步的研究表明，这两类化合物分别通过阻断含溴结构域蛋白 4 (BRD4) 的活性或增加环磷酸腺苷 (cAMP) 水平来抑制 DUX4 信使 RNA (mRNA) 的表达。这些数据揭示了参与体细胞中 DUX4 表达调节的途径，为 FSHD 治疗开发提供了潜在的候选化合物类别，并为可能发现其他治疗靶点的机制研究创造了重要机会。本文的在线版本 (doi:10.1186/s13395-017-0134-x) 包含补充材料，可供授权用户使用。
Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets. The online version of this article (doi:10.1186/s13395-017-0134-x) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Das S;Chadwick BP
通讯作者：
Chadwick BP
选择性抑制BET溴结构域。
影响因子：
64.8
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9.9
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Kissel, JT;McDermott, MP;Kolassa, J
通讯作者：
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作者：
Geng, Linda N.;Tyler, Ashlee E.;Tapscott, Stephen J.
通讯作者：
Tapscott, Stephen J.
影响因子：
3
作者：
BILSKI, AJ;HALLIDAY, SE;WALE, JL
通讯作者：
WALE, JL