Methyltransferase Drug Discovery

甲基转移酶药物发现

• 批准号: 8110584
• 负责人: HAICHING MA
• 金额: $ 55.97万
• 依托单位: REACTION BIOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110584
• 关键词: Acetylation; Animal Cancer Model; Antineoplastic Agents; Area; Azacitidine; Binding; Biological Assay; Biology; Biotechnology; Buffers; Cell Cycle; Cells; Chromatin; Chromatin Modeling; Chromatin Structure; Collaborations; Communities; DNA Methyltransferase Inhibitor; DNA biosynthesis; Databases; Detection; Development; Drug Delivery Systems; Enzyme Kinetics; Enzymes; Epigenetic Process; Evaluation; FDA approved; Family; Filtration; Functional disorder; Funding; Future; Gene Expression; Gold; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Individual; Industry; Inhibitory Concentration 50; Lead; Libraries; Lysine; Malignant Neoplasms; Marketing; Methionine; Methods; Methylation; Methyltransferase; Miniaturization; Modeling; Molecular; Nature; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Positioning Attribute; Post-Translational Protein Processing; Procedures; Process; Production; Proteins; Radioisotopes; Reaction; Regulation; Reporting; Research; Research Activity; Role; Screening procedure; Services; Signal Transduction; Structure; Structure-Activity Relationship; System; Systems Biology; Technology; Testing; Therapeutic Agents; Toxic effect; Tritium; Ubiquitination; Vidaza; Vorinostat; Zolinza; arginine methyltransferase; assay development; base; cell type; commercialization; cost; driving force; drug discovery; enzyme activity; frontier; high throughput screening; histone methyltransferase; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; miniaturize; novel therapeutic intervention; public health relevance; skills; tool; tumorigenesis

DESCRIPTION (provided by applicant): Chromatin assembly and structure is highly regulated during DNA replication, gene expression, and progression through the cell cycle. Dysfunctions of epigenetic factors, including methylation states, are associated with a variety of cancers. Histone methyltransferases (HMTs), including lysine and arginine methyltransferases, are considered a new and important class of drug targets, however high throughput screening (HTS) assay formats are not available and reference inhibitors remain unknown. Establishment of HTS assays and reference compounds would have significant potential to help elucidating the function of these enzymes and to facilitate the development of anticancer agents. Reaction Biology Corporation (RBC) has developed extremely low cost reaction systems for many enzyme classes to serve markets for HTS drug discovery, large scale IC50 determinations and selectivity/toxicity profiling. RBC's HotSpot platform employs a gold standard for ultralow volume radioisotope assays for kinase profiling. This service product for kinase profiling is widely accepted in the drug discovery community for kinase inhibitor development. Based on these skills, RBC is developing a new assay platform using gold standard radioisotope assays for the large family of histone methyltransferases (HMTs). During Phase I, RBC has successfully developed over 13 methyltransferases by using our low cost radioisotope based format. These assays have been validated internally and by customers. We have conducted a trial HTS by using one of the enzymes and identified a few pan-methyltransferase inhibitors that are under further evaluation in both large panel profiling and in cell based assays. Eventually, these compounds could be used as research tools for epigenetic research, which is lacking reference compounds. In Phase II, we propose to expand this technology to add an additional 20 methyltransferases (Aim 1). In Aim 2, HTS campaigns using a 45,000 compound library of diverse structures against the RBC panel of methyltransferase will establish a database to drive structure-activity relationship (SAR) models. In Aim 3, all the individual hits will be profiled for in vitro selectivity and potency, candidates with good activity and clean structures will be further evaluated in cell based assays for methyltransferase inhibition, and lead compounds will go through further SAR studies. Through Phase II funding, RBC will be able to provide HTS and profiling service to cover majority of the human methyltransferases and providing tool compound for research activities. By the end of this funding, RBC will be the major driving force for providing most of the tools needed for epigenetic drug discoveries. After Phase II, RBC will looking for potential collaborations to further SAR studies on the inhibitors that we have discovered in the Phase II screening process. As a result of this funding, drug discovery labs will have access to a new class of industrial grade screening and profiling assays that do not exist today, and protein production in this area will be upgraded as well. PUBLIC HEALTH RELEVANCE: Chromatin assembly and structure is highly regulated during DNA replication, gene expression, and progression through the cell cycle. Dysfunctions of epigenetic factors, including methylation states, are associated with a variety of cancers. Histone methyltransferases (HMTs), including lysine and arginine methyltransferases, are considered a new and important class of drug targets, however high throughput screening (HTS) assay formats are not available and reference inhibitors remain unknown. Establishment of HTS assays and reference compounds would have significant potential to help elucidating the function of these enzymes and to facilitate the development of anticancer agents. Reaction Biology Corporation (RBC) has developed extremely low cost reaction systems for many enzyme classes to serve markets for HTS drug discovery, large scale IC50 determinations and selectivity/toxicity profiling. The HotSpot platform employs a gold standard for ultralow volume radioisotope assays for kinase profiling. This service product for kinase profiling is widely accepted in the drug discovery community for kinase inhibitor development. Based on these skills, RBC seeks to develop a new assay platform using gold standard radioisotope assays for the large family of histone methyltransferases.

描述(由申请人提供)：染色质的组装和结构在DNA复制、基因表达和细胞周期的进展过程中受到高度调控。表观遗传因素的功能障碍，包括甲基化状态，与多种癌症有关。组蛋白甲基转移酶(HMTs)，包括赖氨酸和精氨酸甲基转移酶，被认为是一类新的和重要的药物靶点，然而高通量筛选(HTS)分析模式还不可用，参考抑制剂仍然未知。HTS检测和参考化合物的建立将有助于阐明这些酶的功能，并促进抗癌药物的开发。反应生物学公司(RBC)为许多酶类开发了极低成本的反应系统，以服务于HTS药物发现、大规模IC50测定和选择性/毒性分析市场。RBC的HotSpot平台采用了超低容量放射性同位素分析的黄金标准来分析激酶。这一用于激酶分析的服务产品在用于开发激酶抑制剂的药物发现社区中被广泛接受。基于这些技术，RBC正在开发一种新的分析平台，使用针对组蛋白甲基转移酶(HMTs)大家族的金标准放射性同位素分析。在第一阶段，RBC通过使用我们的低成本放射性同位素形式，成功地开发了13种以上的甲基转移酶。这些检测已经过内部和客户的验证。我们已经通过使用其中一种酶进行了一项HTS试验，并确定了几种泛甲基转移酶抑制剂，这些药物正在大面板分析和基于细胞的分析中进行进一步评估。最终，这些化合物可以作为表观遗传学研究的研究工具，而表观遗传学缺乏参考化合物。在第二阶段，我们建议扩展这项技术，增加20个甲基转移酶(目标1)。在目标2中，HTS活动使用了45,000个不同结构的化合物库来对抗甲基转移酶的RBC小组，将建立一个数据库来驱动结构-活性关系(SAR)模型。在目标3中，将对所有单独的HITS进行体外选择性和效价分析，具有良好活性和干净结构的候选者将在基于细胞的甲基转移酶抑制试验中进一步评估，先导化合物将进行进一步的SAR研究。通过第二阶段的资助，RBC将能够提供HTS和图谱服务，覆盖大部分人类甲基转移酶，并为研究活动提供工具化合物。到这笔资金结束时，RBC将成为提供表观遗传药物发现所需的大多数工具的主要驱动力。在第二阶段之后，RBC将寻找潜在的合作伙伴，以进一步研究我们在第二阶段筛选过程中发现的抑制剂。作为这笔资金的结果，药物发现实验室将获得今天不存在的一类新的工业级筛查和图谱分析，这一领域的蛋白质生产也将得到升级。 与公共健康相关：染色质的组装和结构在DNA复制、基因表达和细胞周期的进展过程中受到高度调控。表观遗传因素的功能障碍，包括甲基化状态，与多种癌症有关。组蛋白甲基转移酶(HMTs)，包括赖氨酸和精氨酸甲基转移酶，被认为是一类新的和重要的药物靶点，然而高通量筛选(HTS)分析模式还不可用，参考抑制剂仍然未知。HTS检测和参考化合物的建立将有助于阐明这些酶的功能，并促进抗癌药物的开发。反应生物学公司(RBC)为许多酶类开发了极低成本的反应系统，以服务于HTS药物发现、大规模IC50测定和选择性/毒性分析市场。HotSpot平台采用了超低容量放射性同位素分析的黄金标准来进行激酶分析。这一用于激酶分析的服务产品在用于开发激酶抑制剂的药物发现社区中被广泛接受。基于这些技能，RBC寻求开发一种新的分析平台，使用组蛋白甲基转移酶大家族的黄金标准放射性同位素分析。