文章：

BET域在肥胖、炎症和癌症中的共同调节作用

BET domain co-regulators in obesity, inflammation and cancer

原文发布日期：2012-06-22

DOI: 10.1038/nrc3256

类型: Review Article

开放获取: 否

要点：

1. Mammalian BET proteins, a class of transcriptional co-regulators that contain dual, mutually related bromodomain motifs and an extraterminal domain, are important in the control of networks of genes; these proteins bind to acetylated lysines in the histones of nucleosomal chromatin, recruit chromatin-modification enzymes to target promoters and function as co-activators or co-repressors of gene expression, depending on the context.
2. New small-molecule inhibitors have recently been developed that disrupt the binding interface between the bromodomain and the acetylated lysine groups; the inhibitors have remarkable potency, selectivity and are well tolerated. They have recently been used as anticancer and anti-inflammatory agents.
3. These developments are important because chromatin was not considered to be a druggable target; as a result of these new drugs, a whole field of new epigenetically targeted therapeutics has become available for investigation.
4. As this field of therapeutics rapidly expands, several features of BET protein function will need to be considered, including possible redundancy among the closely related family members, the selectivity of next-generation agents for specific BET proteins, and possible undesirable consequences of systemic administration without cellular targeting. These side effects might include uncontrolled transcriptional derepression of genes, altered haematopoiesis, immunosuppression or reactivation of latent viruses.

要点翻译：

1. 哺乳动物BET蛋白是一类转录共调节因子，含有两个相互关联的溴结构域基序和一个末端外结构域，在基因网络调控中具有重要作用。这些蛋白可与核小体染色质组蛋白中乙酰化的赖氨酸结合，将染色质修饰酶招募至靶启动子，并根据具体情境作为基因表达的共激活因子或共抑制因子发挥作用。
2. 近期研发的新型小分子抑制剂能破坏溴结构域与乙酰化赖氨酸基团之间的结合界面，这些抑制剂具有显著效力、高选择性且耐受性良好，目前已被应用于抗癌和抗炎治疗。
3. 这些进展具有重要意义，因为染色质此前并未被视为可成药靶点。基于这些新药的问世，表观遗传靶向治疗的全新研究领域已开启。
4. 随着该治疗领域的快速扩展，我们需要综合考虑BET蛋白功能的若干特性：包括高度同源家族成员间可能存在的功能冗余、新一代药物对特定BET蛋白的选择性，以及全身给药缺乏细胞靶向性可能引发的不良后果。这些副作用可能包括基因转录抑制的失控、造血功能改变、免疫抑制或潜伏病毒的再激活。

英文摘要：

The bromodomain is a highly conserved motif of 110 amino acids that is bundled into four anti-parallel α-helices and found in proteins that interact with chromatin, such as transcription factors, histone acetylases and nucleosome remodelling complexes. Bromodomain proteins are chromatin 'readers'; they recruit chromatin-regulating enzymes, including 'writers' and 'erasers' of histone modification, to target promoters and to regulate gene expression. Conventional wisdom held that complexes involved in chromatin dynamics are not 'druggable' targets. However, small molecules that inhibit bromodomain and extraterminal (BET) proteins have been described. We examine these developments and discuss the implications for small molecule epigenetic targeting of chromatin networks in cancer.

摘要翻译： 

溴结构域是一个由110个氨基酸组成的高度保守基序，折叠成四束反平行α螺旋，存在于与染色质相互作用的蛋白质中，如转录因子、组蛋白乙酰化酶和核小体重塑复合物。溴结构域蛋白是染色质的“阅读器”；它们招募染色质调控酶（包括组蛋白修饰的“书写器”和“擦除器”）至靶启动子，从而调控基因表达。传统观点认为，参与染色质动态调控的复合物是不可成药的靶点。然而，已有小分子抑制剂可靶向溴结构域和末端外（BET）蛋白。本文综述这些进展，并讨论小分子表观遗传靶向染色质网络在癌症治疗中的意义。

原文链接：

BET domain co-regulators in obesity, inflammation and cancer