Synthesis of Small-Molecule Inhibitors Targeting Bromodomain Containing Proteins

靶向含溴结构域蛋白的小分子抑制剂的合成

• 批准号: 533881-2018
• 负责人: Gagnon, Alexandre
• 金额: $ 1.82万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=651344
• 关键词: Synthesis; Small; Molecule; Inhibitors; Targeting

The genetic information of an organism is contained within its DNA sequence. In order to fit inside the nucleus of a cell, DNA wraps itself around an octamer of proteins called histones, resulting in formation of chromatin. Epigenetic transformations, which consist in the installation of marks on DNA and histone tails, affect the level of compaction of chromatin, resulting in gene activation or silencing. Lysine acetylation is an epigenetic transformation that leads to the removal of the positive charge on the amino group of the lysine side chain thus preventing the formation of electrostatic interactions with the phosphate groups of DNA and resulting in gene transcription. Bromodomains are reader epigenetic proteins that bind to acetylated lysines to recruit transcription factors and promote gene transcription. A few bromodomain inhibitors have been reported and used as chemical probes to better understand the role of these proteins in chromatin remodeling and gene expression. However, because these compounds are all chemically related, they present similar liabilities in terms of target specificity and biopharmaceutical properties. Zenith Epigenetics is a biotechnology company with an expertise on the development of bromodomain inhibitors. To maintain their competitiveness, they must identify new targets and novel compounds that interact with them to modulate their activity. Recently, a new bromodomain containing protein (BCP) has been identified by Zenith Epigenetics, along with two molecules that bind to these proteins to interfere with their function. However, the chemical complexity of these compounds and the preparation of derivatives with increased potency requires an advanced expertise in organic synthesis and in medicinal chemistry. The goal of this project is to design and synthesize potent and selective inhibitors of BCPs that will serve as chemical probes to investigate the biochemical role of these proteins in chromatin remodeling and gene expression.**********

生物体的遗传信息包含在其DNA序列中。为了进入细胞核，DNA将自身包裹在一种称为组蛋白的八聚体周围，从而形成染色质。表观遗传转化，包括在DNA和组蛋白尾部上安装标记，影响染色质的压实水平，导致基因激活或沉默。赖氨酸乙酰化是一种表观遗传转化，其导致赖氨酸侧链的氨基上的正电荷的去除，从而防止与DNA的磷酸基团形成静电相互作用并导致基因转录。溴结构域是与乙酰化赖氨酸结合以募集转录因子并促进基因转录的阅读器表观遗传蛋白。一些布罗莫结构域抑制剂已被报道并用作化学探针，以更好地了解这些蛋白质在染色质重塑和基因表达中的作用。然而，由于这些化合物都是化学相关的，它们在靶向特异性和生物制药性质方面存在类似的责任。Zenith Epigenetics是一家生物技术公司，专门从事溴结构域抑制剂的开发。为了保持其竞争力，它们必须确定新的靶标和与它们相互作用以调节其活性的新化合物。最近，Zenith Epigenetics已经鉴定了一种新的含溴结构域蛋白（BCP），沿着两种分子与这些蛋白质结合以干扰其功能。然而，这些化合物的化学复杂性和具有增加效力的衍生物的制备需要有机合成和药物化学方面的先进专业知识。该项目的目标是设计和合成BCP的有效和选择性抑制剂，这些抑制剂将作为化学探针来研究这些蛋白质在染色质重塑和基因表达中的生化作用。