Identify small molecule inhibitors of methyl-dependent protein-protein interactio

鉴定甲基依赖性蛋白质-蛋白质相互作用的小分子抑制剂

• 批准号: 8011493
• 负责人: MARK T. BEDFORD
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011493
• 关键词: Affinity; Ankyrin Repeat; Area; Binding; Biological; Biological Assay; Calorimetry; Cells; Chemicals; Chimeric Proteins; Chromatin; Collaborations; Collection; Confocal Microscopy; Credentialing; Development; Digit structure; Disease; Docking; Enzymes; Epigenetic Process; Fluorescence Polarization; Fluorescence Resonance Energy Transfer; Gene Mutation; Gene Silencing; Genomics; Glass; Goals; Histone H3; In Vitro; Intervention; Lead; Lysine; Malignant Neoplasms; Methylation; Methyltransferase; Miniaturization; Nature; Neurons; Pathway interactions; Peptides; Permeability; Pharmacotherapy; Problem Solving; Protein Methyltransferases; Protein Microchips; Proteins; Publications; Reading; Side; Signal Transduction; Site; Solutions; Specificity; Staging; Surface Plasmon Resonance; Techniques; Technology; Tertiary Protein Structure; Testing; Titrations; United States National Institutes of Health; analog; arm; base; cancer therapy; design; drug development; follow-up; frontier; high throughput screening; inhibitor/antagonist; nervous system disorder; prevent; protein protein interaction; public health relevance; research study; small molecule; stoichiometry

DESCRIPTION (provided by applicant): As our understanding of epigenetics expands, it is becoming clear that players in this field are potential targets for drug development. This area of epigenetic therapy has established applications for the treatment of cancer and neurological diseases. We have been involved in this field for a number of years and have performed high-throughput screens to identify the first small molecule inhibitors of protein methyltransferases. These methyltransferases target multiple substrates, and thus regulate many arms of an epigenetic pathway. The methylation of different substrates often generates docking sites for effector protein that harbor domains (chromo, tudor, PHD, MBT and ANK repeats). We hypothesize that by inhibiting specific protein-protein interactions we will be able to develop compounds that block a single arm of an epigenetic pathway. The specificity attained by blocking a single protein-protein interaction will be far greater than that attained by blocking the enzyme that regulates one of many interactions. Low-affinity protein-protein interactions (Kd in the single- to double-digit micromolar range) such as those discussed here have been very difficult to assay by traditional techniques such as fluorescence polarization or fluorescence resonance energy transfer. We have solved this problem by developing a sensitive chemiluminescence-based assay, which serves as the starting point for this project. Here we plan to perform screens to identify lead compounds that can block methyl- dependent protein-protein interactions, which can be used as probes to analyze these methyl-driven interactions and perhaps even developed into targeted epigenetic therapies. ) PUBLIC HEALTH RELEVANCE: Epimutations, unlike genetic mutations, can be reversed by chemotherapeutic intervention, which makes epigenetic therapy conceptually extremely appealing. Drug therapies that target chromatin have been touted as the next emerging frontier for the treatment of cancer and neuronal-based diseases. In this study, we will identify small molecules that will prevent these epimutations from being read.

描述(由申请人提供)：随着我们对表观遗传学的了解的扩大，这一领域的参与者是药物开发的潜在目标变得越来越明显。表观遗传疗法的这一领域已被应用于癌症和神经系统疾病的治疗。我们已经在这个领域从事了多年，并进行了高通量筛选，以确定第一个蛋白质甲基转移酶的小分子抑制剂。这些甲基转移酶以多种底物为靶标，从而调节表观遗传途径的许多臂。不同底物的甲基化通常为含有结构域(chromo、Tudor、PHD、MBT和ANK重复)的效应蛋白生成对接位置。我们假设，通过抑制特定的蛋白质-蛋白质相互作用，我们将能够开发出阻断表观遗传途径的单臂的化合物。阻断单一蛋白质-蛋白质相互作用所获得的特异性将远远大于阻断调节许多相互作用中的一种的酶所获得的特异性。低亲和力的蛋白质-蛋白质相互作用(Kd在一到两位数的微摩尔范围内)，如这里讨论的那些，已经很难用传统的技术，如荧光偏振或荧光共振能量转移来测定。我们已经解决了这个问题，开发了一种基于化学发光的灵敏分析方法，作为本项目的起点。在这里，我们计划进行筛选，以确定可以阻止甲基依赖的蛋白质-蛋白质相互作用的先导化合物，这些化合物可以用作探针来分析这些甲基驱动的相互作用，甚至可能发展成有针对性的表观遗传疗法。) 与公共卫生相关：与基因突变不同，表观突变可以通过化疗干预来逆转，这使得表观遗传疗法在概念上非常有吸引力。针对染色质的药物疗法被吹捧为治疗癌症和神经性疾病的下一个新兴前沿。在这项研究中，我们将识别阻止这些表位突变被读取的小分子。