Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell & Development Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Stem Cell & Development Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
J Mol Biol. 2017 Jun 30;429(13):2003-2010. doi: 10.1016/j.jmb.2016.11.020. Epub 2016 Nov 24.
Lysine acetylation of histone proteins is a fundamental post-translational modification that regulates chromatin structure and plays an important role in gene transcription. Aberrant levels of histone lysine acetylation are associated with the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are structurally conserved modules present in transcription-associated proteins that are termed "reader" proteins. Bromodomain-containing reader proteins are part of multiprotein complexes that regulate transcription programs, which are often associated with profound phenotypic changes. Many bromodomain-containing proteins are aberrantly expressed in diseases, as best studied in cancers, where bromodomain proteins impact the expression of oncogenes and anti-apoptotic proteins. Thus, bromodomain readers of histone acetylation have emerged as attractive targets for cancer drug discovery, prompting immense interest in epigenetic-focused, medicinal chemistry to develop structurally guided chemical probes of bromodomains. Here, we describe bromodomain-containing proteins with defined roles in cancer and highlight recent progress in the development of bromodomain inhibitors.
组蛋白赖氨酸乙酰化是一种基本的翻译后修饰，它调节染色质结构，在基因转录中发挥重要作用。组蛋白赖氨酸乙酰化水平异常与多种疾病的发生有关。乙酰化赖氨酸修饰为溴结构域创造了停靠位点，溴结构域是存在于与转录相关的蛋白质中的结构保守模块，被称为“读取器”蛋白。含有溴结构域的读取器蛋白是调节转录程序的多蛋白复合物的一部分，这些复合物通常与明显的表型变化有关。在疾病中，许多含有溴结构域的蛋白质表达异常，在癌症中研究得最多，其中溴结构域蛋白影响癌基因和抗细胞凋亡蛋白的表达。因此，组蛋白乙酰化的溴结构域读取器已成为癌症药物发现的有吸引力的靶点，这促使人们对以表观遗传学为重点的药物化学产生了巨大的兴趣，以开发结构导向的溴结构域化学探针。在这里，我们描述了在癌症中具有明确作用的含有溴结构域的蛋白质，并强调了溴结构域抑制剂开发方面的最新进展。
