Methyltransferase Drug Discovery

甲基转移酶药物发现

• 批准号: 7663498
• 负责人: HAICHING MA
• 金额: $ 17.07万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663498
• 关键词: Acetylation; Animal Model; Antineoplastic Agents; Azacitidine; Basic Science; Binding; Biological Assay; Biology; Biotechnology; Buffers; Cell Cycle; Cells; Chemicals; Cherry - dietary; Chromatin; Chromatin Modeling; Communities; DNA Methyltransferase Inhibitor; DNA biosynthesis; Data; Detection; Development; Drug Delivery Systems; Enzyme Kinetics; Enzymes; Epigenetic Process; FDA approved; Family; Filtration; Functional disorder; Funding; Gene Expression; Goals; Gold; Histone Deacetylase Inhibitor; Histone-Lysine N-Methyltransferase; Histones; Human; Industry; Inhibitory Concentration 50; Lead; Libraries; Malignant Neoplasms; Marketing; Methods; Methylation; Methyltransferase; Miniaturization; Molecular; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Procedures; Process; Protocols documentation; Radioisotopes; Reaction; Regulation; Research; Research Project Grants; Role; S-Adenosylmethionine; Screening procedure; Services; Signal Transduction; Structure; Structure-Activity Relationship; System; Systems Biology; Technology; Testing; Toxic effect; Tritium; Ubiquitination; United States National Institutes of Health; Validation; Vidaza; Vorinostat; Work; Zolinza; assay development; base; cost; cost effective; drug discovery; enzyme activity; frontier; high throughput screening; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; miniaturize; nanolitre; novel therapeutic intervention; public health relevance; repository; skills; therapeutic development; tumorigenesis

DESCRIPTION (provided by applicant): Chromatin assembly and structure is highly regulated during DNA replication, gene expression, and progression through the cell cycle. Dysfunction of epigenetic factors, including methylation state, are associated with a variety of cancers. Histone lysine methyltransferases (HKMTs) 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. HTS assays and reference compounds would have significant potential to help elucidate 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 ultra high throughput screening (uHTS) 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 lysine methyltransferases (HKMTs). Through Phase I funding, the proposed research will focus on the following three aims: Aim 1 Develop a universal radioisotope-based gold standard for HKMTs with large signal/background ratio; Aim 2 Reduce assay costs by ultra-miniaturization and streamline assay protocols for robust HTS; Aim 3 Conduct HTS and identify new compounds for an HKMT using assays developed in Aims 1 and 2 by screening the libraries from RBC's chemical repository. This work will enable Phase II activities where RBC will expand its assay range across the large human HKMTs family and use this newly developed universal assay against large synthetic and natural compound libraries to discover potential molecules for research and therapeutic development. Selected lead compounds will be evaluated in cell based assays for anti-cancer activities PUBLIC HEALTH RELEVANCE: Chromatin assembly and structure is highly regulated during DNA replication, gene expression, and progression through the cell cycle. Dysfunction of epigenetic factors, including methylation state, are associated with a variety of cancers. Histone lysine methyltransferases are considered a new and important class of drug targets, however high throughput screening assay formats are not available and reference inhibitors remain unknown. HTS assays and reference compounds would have significant potential to help elucidate function of these enzymes and to facilitate the development of anticancer agents. Reaction Biology Corporation has developed extremely low cost reaction systems for many enzyme classes to serve markets for ultra high throughput screening 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 lysine methyltransferases.

描述（由申请人提供）：染色质组装和结构在DNA复制、基因表达和细胞周期进程中受到高度调节。表观遗传因子的功能障碍，包括甲基化状态，与多种癌症相关。组蛋白赖氨酸甲基转移酶（HKMT）被认为是一类新的和重要的药物靶点，然而高通量筛选（HTS）测定格式不可用，参考抑制剂仍然未知。HTS测定和参考化合物将具有重要的潜力，以帮助阐明这些酶的功能，并促进抗癌药物的开发。Reaction Biology Corporation（RBC）已经为许多酶类别开发了极低成本的反应系统，以服务于超高通量筛选（uHTS）药物发现、大规模IC 50测定和选择性/毒性分析的市场。HotSpot平台采用金标准进行超低容量放射性同位素测定，用于激酶分析。这种激酶分析服务产品在激酶抑制剂开发的药物发现社区中被广泛接受。基于这些技能，RBC寻求开发一个新的检测平台，使用金标准放射性同位素检测组蛋白赖氨酸甲基转移酶（HKMT）的大家族。透过第一期拨款，拟议研究将集中于以下三个目的：目的1发展一个通用的以放射性同位素为基础的金标准，以供香港中期测试使用，并具有大信号/背景比;目的2透过超微型化及精简分析程序，以减低分析成本，从而提供可靠的高温超导测试;目标3通过筛选RBC化学库中的库，使用目标1和2中开发的测定法进行HTS并鉴定HKMT的新化合物。这项工作将使第二阶段的活动，其中RBC将扩大其在大型人类HKMT家族的检测范围，并使用这种新开发的通用检测方法对大型合成和天然化合物库，以发现潜在的分子进行研究和治疗开发。选定的先导化合物将在基于细胞的抗癌活性测定中进行评估公共健康相关性：染色质组装和结构在DNA复制、基因表达和细胞周期进展过程中受到高度调节。表观遗传因子的功能障碍，包括甲基化状态，与多种癌症相关。组蛋白赖氨酸甲基转移酶被认为是一类新的和重要的药物靶标，然而高通量筛选测定形式不可用，并且参考抑制剂仍然未知。HTS测定和参考化合物将具有重要的潜力，以帮助阐明这些酶的功能，并促进抗癌药物的开发。Reaction Biology Corporation为许多酶类别开发了极低成本的反应系统，以服务于超高通量筛选药物发现，大规模IC 50测定和选择性/毒性分析的市场。HotSpot平台采用金标准进行超低容量放射性同位素测定，用于激酶分析。这种激酶分析服务产品在激酶抑制剂开发的药物发现社区中被广泛接受。基于这些技能，RBC寻求开发一个新的检测平台，使用金标准放射性同位素检测组蛋白赖氨酸甲基转移酶大家族。