Synthesis of Small-Molecule Inhibitors Targeting Bromodomain Containing Proteins

生物体的遗传信息包含在其DNA序列中。为了适合进入细胞核，DNA将自己包裹在一种称为组蛋白的蛋白质的八聚体周围，从而形成染色质。表观遗传转化包括在DNA和组蛋白尾巴上安装标记，影响染色质的紧致程度，导致基因激活或沉默。赖氨酸乙酰化是一种表观遗传转化，它导致赖氨酸侧链上氨基上的正电荷被移除，从而阻止与DNA的磷酸基团形成静电相互作用，从而导致基因转录。溴域是一种阅读器表观遗传蛋白，它与乙酰化赖氨酸结合，招募转录因子，促进基因转录。一些溴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，它们在靶标特异性和生物制药特性方面呈现出类似的风险。Zenith Eigenetics是一家生物技术公司，在溴域抑制剂的开发方面拥有专业知识。为了保持它们的竞争力，它们必须确定新的靶点和新的化合物，与它们相互作用，以调节它们的活动。最近，Zenith epigenetics发现了一种新的含有溴域的蛋白质(BCP)，以及两个与这些蛋白质结合的分子来干扰它们的功能。然而，这些化合物的化学复杂性以及提高效力的衍生物的制备需要在有机合成和药物化学方面的高级专业知识。这个项目的目标是设计和合成有效的和选择性的BCP抑制剂，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。

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.**********