Epigenetic Probes for HMTs

HMT 表观遗传探针

• 批准号: 9247927
• 负责人: HAICHING MA
• 金额: $ 76.47万
• 依托单位: REACTION BIOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247927
• 关键词: Acetylation; Animal Cancer Model; Area; Binding; Binding Proteins; Biochemical; Biological; Biological Assay; Biological Process; Biology; Blood; Bromodomain; Cardiovascular Diseases; Cells; Chemicals; Clinical Pharmacology; Clinical Trials; Collaborations; Collection; DNA Sequence Alteration; Data; Databases; Development; Disease; Drug Targeting; Effectiveness; Enzymes; Epigenetic Process; FDA approved; Funding; Genomics; Goals; Histones; In Vitro; Individual; Investigation; Kinetics; Laboratory Research; Lead; Libraries; Malignant Neoplasms; Medicine; Metabolic Diseases; Methods; Methylation; Natural Products; Neurodegenerative Disorders; Oral; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Preclinical Drug Evaluation; Property; Protein Family; Proteins; Publishing; Radioisotopes; Reaction; Reference Standards; Research; Role; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; Testing; Therapeutic Agents; Toxic effect; Universities; Validation; analog; base; commercialization; drug development; drug discovery; epigenomics; histone methylation; histone methyltransferase; improved; in vivo; inhibitor/antagonist; nanomolar; new technology; new therapeutic target; phase 1 study; public health relevance; scaffold; screening; small molecule; small molecule inhibitor; symptom treatment; therapeutic effectiveness; tool

 DESCRIPTION (provided by applicant): Epigenetic proteins, such as histone methyltransferases represent important potential drug targets for indications like cancers, neurodegenerative disorders, and cardiovascular and metabolic diseases. At Reaction Biology Corporation ("RBC"), we are working toward the complete coverage of all epigenetic targets, including HMTs, to identify and improve epigenetic modulators that can be used in research and drug discovery. In this Phase II application, we have proposed three aims following successful Phase I studies to continue the understanding of HMTs' biological functions and as new drug targets. The aims include 1) Complete the screening of HMTs for identifying new probes and building the chemical-epigenetic data base; 2) Broader HTS and Structure-Activity Relationship (SAR) study to identify and increase the potency of NSD inhibitors; and 3) Evaluating NSD inhibitors' efficacy in cell based assays, and determining their kinetic MOAs and early DMPK/tox profiles. We'll meet the following milestones: (1) Develop and commercialize 10 or more HMT probes as general research tools for at least 5 HMTs; 2) Improve at least 2 lead compounds' potency into the nanomolar range against NSDs that have different structure scaffolds, with good cell based activity and DMPK profiles; and (3) we will be able to launch one of the largest publicly available chemical-epigenetic data bases built on the screening activities from the compound collections that include most of the FDA approved drugs, clinical trial agents, diversified libraries, and natural products.

 描述（由申请人提供）：表观遗传蛋白，如组蛋白甲基转移酶，代表了癌症、神经退行性疾病以及心血管和代谢疾病等适应症的重要潜在药物靶点。在Reaction Biology Corporation（“RBC”），我们正致力于完全覆盖所有表观遗传靶点，包括HMT，以鉴定和改进可用于研究和药物发现的表观遗传调节剂。在第二阶段的申请中，我们提出了三个目标，继成功的第一阶段研究，以继续了解HMT的生物学功能和作为新的药物靶点。目标包括1）完成HMT的筛选以鉴定新探针并建立化学-表观遗传数据库; 2）更广泛的HTS和结构-活性关系（SAR）研究以鉴定和增加NSD抑制剂的效力;和3）在基于细胞的测定中评估NSD抑制剂的功效，并确定其动力学MOA和早期DMPK/tox概况。我们将实现以下里程碑：（1）开发并商业化10个或更多个HMT探针，作为至少5个HMT的通用研究工具; 2）将至少2个先导化合物针对具有不同结构支架的NSD的效力提高到纳摩尔范围，具有良好的基于细胞的活性和DMPK谱;和（3）我们将能够推出一个最大的公开可用的化学表观遗传数据库，该数据库建立在从化合物集合中筛选活动的基础上，这些化合物集合包括大多数FDA批准的药物，临床试验药物，多样化的图书馆和天然产物。