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Product Development for Bromodomain Networks

Bromodomain 网络的产品开发

基本信息

批准号：
9253938
负责人：
HAICHING MA
金额：
$ 84.88万
依托单位：
REACTION BIOLOGY CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9253938
关键词：
Animal Model Area Binding Binding Proteins Biological Biological Assay Biology Blood Bromodomain Categories Cell physiology Cells Chemicals Chromatin Clinical Clinical Pharmacology Clinical Trials Collection DNA Sequence Alteration Data Databases Drug Targeting Effectiveness Epigenetic Process FDA approved Family Fluorescence Polarization Funding Gene Expression Regulation Goals Grant Histones Human In Vitro Inflammation Kinetics Knowledge Lead Libraries Lysine Malignant Neoplasms Maps Methyltransferase Modification Pharmaceutical Preparations Phase Phosphotransferases Process Production Protein Family Proteins Public Domains Publishing Reaction Reader Reagent Research Resources Rest Scientist Services Small Business Innovation Research Grant Structure-Activity Relationship Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Toxic effect United States National Institutes of Health Work analog assay development base chromatin modification commercialization drug discovery epigenetic regulation experience follow-up histone methyltransferase human disease improved in vivo inhibitor/antagonist interest new technology product development scaffold screening success therapeutic effectiveness

项目摘要

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.

Bromo域网络公司的产品开发：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，对于正常的细胞功能是必不可少的。然而，它也会导致人类疾病，如癌症和炎症。参与的蛋白质家族表观遗传调控包括共价修饰染色质的编写体；识别染色质修饰的阅读器；和橡皮擦，可以移除修改。过去十年来该领域的大量研究表明，许多表观遗传蛋白是潜在的可用药靶点。属于阅读器类别的溴域识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域化合物最近被发现，增加了对功能重要性和治疗潜力的认识。这个家庭。然而，研究是有限的，而且只集中在几个溴结构域亚家族，如溴结构域和端外(BET)蛋白。这些研究没有扩展到更多的读者蛋白，原因有很多；关键的限制在于产品的可用性和这些非BET子家族目标的知识体系。作为拟议的第二阶段申请的一部分，我们将集中进行三项主要工作：1)完成对针对FDA批准的药物和NIH的临床试验试剂集合的溴域，用于识别新的探针和建立化学-表观遗传学数据库；2)扩大HTS努力，将4至7个新的BRD纳入潜在药物目标。这些溴结构域将是很好的潜在药物靶点，但没有探针或缺乏基于公共领域信息；以及3)通过SAR研究开发有效和选择性的探针，并评估其在细胞中的活性基础化验。具有独特支架的先导化合物将作为潜在的DMPK-Tox分析进行进一步测试治疗剂。