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

基本信息

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

项目摘要

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。为了适合细胞细胞核内，DNA将自身包裹在一个称为组蛋白的蛋白质的八聚体周围，从而形成染色质。表观遗传转化由DNA和组蛋白尾巴上的标记的安装组成，会影响染色质压实水平，从而导致基因激活或沉默。赖氨酸乙酰化是一种表观遗传转化，可导致赖氨酸侧链的氨基中的阳性电荷去除，从而阻止了与DNA的磷酸盐相互作用的形成，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读取器表观遗传蛋白。已经报道并将一些溴结构域抑制剂用作化学探针，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。但是，由于这些化合物都是化学相关的，因此在目标特异性和生物制药特性方面，它们具有相似的责任。 Zenith表观遗传学是一家生物技术公司，在溴生型域抑制剂的发展方面具有专业知识。为了保持竞争力，他们必须确定与他们相互作用的新目标和新颖的化合物以调节其活动。最近，Zenith表观遗传学鉴定出一种新的含有蛋白质的溴结构域（BCP），以及与这些蛋白质结合以干扰其功能的两个分子。但是，这些化合物的化学复杂性以及具有效力提高的衍生物的制备需要有机合成和药物化学方面的高级专业知识。该项目的目的是设计和合成BCP的有效和选择性抑制剂，这些抑制剂将用作化学探针，以研究这些蛋白质在染色质重塑和基因表达中的生化作用。****************