Epigenetic Probes for HMTs

 描述(申请人提供)：表观遗传蛋白，如组蛋白甲基转移酶，是治疗癌症、神经退行性疾病、心血管和代谢性疾病等适应症的重要潜在药物靶点。在反应生物学公司(“RBC”)，我们正在努力实现包括HMT在内的所有表观遗传靶点的全面覆盖，以识别和改进可用于研究和药物发现的表观遗传调节剂。在这一第二阶段的应用中，我们在第一阶段研究成功后提出了三个目标，以继续了解HMT的生物学功能并作为新的药物靶点。目标包括1)完成HMT的筛选，以确定新的探针并建立化学-表观遗传学数据库；2)更广泛的HTS和构效关系(SAR)研究，以识别和提高NSD抑制剂的效力；以及3)在基于细胞的分析中评估NSD抑制剂的有效性，并确定它们的动力学MOA和早期DMPK/TOX谱。我们将实现以下里程碑：(1)开发10个或更多HMT探针并将其商业化，作为至少5个HMT的通用研究工具；2)将至少2种先导化合物的效力提高到纳摩尔范围，以对抗具有不同结构支架、具有良好细胞活性和DMPK图谱的NSD；以及(3)我们将能够推出基于化合物集合筛选活动的最大公开可用化学表观遗传学数据库之一，其中包括大多数FDA批准的药物、临床试验药物、多样化的文库和天然产品。

 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.