Product Development for Bromodomain Networks

Bromodomain Networks的产品开发： 摘要： 基因表达的表观遗传调控是一个高度动态和可逆的过程，对正常细胞功能至关重要。 然而，它也有助于人类疾病，如癌症和炎症。蛋白质家族参与 表观遗传调控包括共价修饰染色质的写入器，识别染色质修饰的读取器， 和擦除器，其去除修改。在过去十年中，该领域的大量研究表明， 表观遗传蛋白是潜在的药物靶点。Bromodomains属于读者类别， 组蛋白和其他蛋白质上的乙酰化赖氨酸残基。几种有效的、选择性的和细胞活性的溴结构域 最近已经鉴定了化合物，增加了对化合物的功能重要性和治疗潜力的认识。 这个家然而，研究是有限的，并且仅集中于少数溴结构域亚家族，例如溴结构域和溴结构域。 末端外（BET）蛋白。这些研究没有扩展到更多的阅读器蛋白有很多原因; 关键的限制在于产品的可用性和这些非BET亚族靶的知识体系。 作为第二阶段申请的一部分，我们将集中精力进行三项主要工作：1）完成 溴结构域针对FDA批准的药物和NIH的临床试验试剂集合，用于鉴定新的探针， 建立化学-表观遗传学数据库; 2）扩大HTS工作，将4至7种新的BRD作为潜在药物 目标的这些布罗莫结构域将是良好的潜在药物靶标，但没有探针或缺乏基于布罗莫结构域的良好探针。 公开领域的信息; 3）通过SAR研究开发有效的和选择性的探针，并评估它们在细胞中的活性 基于分析。具有独特支架的先导化合物将进一步用DMPK-Tox测定法进行测试， 治疗剂。

Product Development for Bromodomain Networks: Abstract: Epigenetic regulation of gene expression is a highly dynamic and reversible process essential to normal cellular function. However, it also contributes to human diseases, such as cancer and inflammation. Protein families that participate in epigenetic regulation include writers, which covalently modify chromatin; readers, which recognize chromatin modifications; and erasers, which remove modifications. A large volume of research in the field over the past decade has shown that many epigenetic proteins are potential druggable targets. Bromodomains, which belong to the readers category, recognize acetylated lysine residues on histones and other proteins. Several potent, selective and cellularly active bromodomain compounds have recently been identified, increasing appreciation of the functional importance and therapeutic potential of this family. However, studies are limited and focus only on a few bromodomain subfamilies, such as the bromodomain and extraterminal (BET) proteins. There are a number of reasons that the studies have not expanded into more reader proteins; the key limitations are in both the availabilities of products and the body of knowledge for these non-BET subfamily targets. As part of the proposed Phase II application we’ll concentrate on 3 major works: 1) to complete the screening of Bromodomains against the FDA approved drugs and NIH’s clinical trial agent collections for identifying new probes and building the chemical-epigenetic data base; 2) to expand the HTS efforts to include 4 to 7 new BRDs as potential drug targets. These bromodomains will be good potential drug targets, but have no probes or lack of good probes based on public domain information; and 3) to develop potent and selective probes by SAR studies and evaluate their activities in cell based assays. The lead compounds with unique scaffolds will be further tested with DMPK-Tox assays as potential therapeutic agents.