Mechanism-based small molecule epigenetic modulators: Targeting specific HDACs

基于机制的小分子表观遗传调节剂：针对特定 HDAC

• 批准号: 7936828
• 负责人: LIN CHEN
• 金额: $ 50万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936828
• 关键词: Address; Affinity; Alzheimer' s Disease; Area; Binding; Binding Sites; Biochemical; Biological Markers; Biology; Blood; Blood Vessels; Cardiac; Cardiovascular system; Catalytic Domain; Chemicals; Chemistry; Chromatin; Chromatin Structure; Collaborations; Complex; DNA Binding; Data; Development; Diagnostic; Disease; Disease model; Enzymes; Epigenetic Process; Event; Family; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Goals; HDAC4 gene; Heart; Heart Hypertrophy; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Image; Immune; In Vitro; Inflammation; Inhibitory Concentration 50; Intervention; Lead; Lung; Malignant Neoplasms; Mediating; Medicine; Methodology; Methods; Modeling; Molecular; Molecular Probes; Molecular Target; Muscle; Muscle Cells; Nerve Degeneration; Neurodegenerative Disorders; Neurons; New Agents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Principal Investigator; Property; Proteins; Reagent; Regulation; Research; Respiratory System; Respiratory tract structure; Role; Series; Source; Structure; T-Lymphocyte; Technology; Therapeutic; Therapeutic Effect; Validation; Work; Zinc; age related; base; cancer therapy; clinically relevant; design; drug development; drug discovery; experience; human disease; in vivo; inhibitor/antagonist; insight; interest; member; myocyte-specific enhancer-binding factor 2; new technology; novel; novel strategies; programs; promoter; protein protein interaction; public health relevance; response; small molecule; structural biology; tool; transcription factor

DESCRIPTION (provided by applicant): The increasing recognition of the importance of epigenetic regulation of gene expression for numerous areas of biology and medicine has led to a growing interest in this field. Despite many advances, our understanding of the molecular aspects involved in epigenetic events is still lacking and there is a growing demand for new approaches and new molecular tools to enable future advances in this field. The majority of current small molecule modulators of epigenetic regulators work by binding to the catalytic site of enzymes that modify chromatin. Because the catalytic site is often shared by multiple enzymes with distinct cellular roles, a major challenge in this area of research has been the lack of small molecules that can target a specific enzyme, which would greatly facilitate the study of the basic mechanism of epigenetic regulation and may lead to more specific and effective therapeutics. The long term objective of the research proposed in the present application is to explore a different mode of intervention of epigenetic regulators, namely by targeting protein-protein interaction in their regulatory complexes. Specifically, small molecule inhibitors will be developed for a subclass of histone deacetylases (class IIa HDACs) that are highly expressed in T cells, neurons, and muscle and are potential targets of HDAC inhibitors that showed beneficial effects in inflammation, neurodegenerative disorders, and cardiac hypertrophy The overall strategy of this proposal is to search for small molecules that block the binding of class IIa HDACs to their functional transcription factor partner, using the MEF2/HDAC interaction as a way to establish a proof of principle. Towards this goal the two principal investigators will rely on their extensive and complementary experience in structural biology and synthetic/medicinal chemistry to identify and utilize relevant molecular aspects of this problem, including: the vast amount of functional data on existing HDAC inhibitors, the availability of detailed biochemical and structural information on MEF2/HDAC interaction, and the utilization of novel chemistry-based methodologies. The basic approach is to combine structure-based modeling, targeted screen, and structure-function validation to search for such subclass specific HDAC inhibitors. Using this approach, preliminary studies have already identified several promising small molecule inhibitors of this type, that will be investigated in detail. The proposed research will further characterize the functions and properties of these molecules and establish the basis for developing new molecular probes to study HDAC function, including imaging agents and new leads for potential therapeutics for a number of major diseases. Overall, the proposed studies will serve as an example to address the feasibility of blocking protein- protein interaction in regulatory complexes as an approach to developing chemical modulators of epigenetic regulators. The new small molecule modulators of HDAC function that will be developed, are expected to be subtype specific and should help make multiple advances in the increasingly important and still emerging field of epigenetics, as well as its many applications in several disease areas. These studies will also provide new tools to study key target genes that could serve as biomarkers for diseases in the neuronal, immune and cardiovascular systems. Mechanism-based small molecule epigenetic modulators: Targeting specific HDACs PUBLIC HEALTH RELEVANCE: This application addresses broad Challenge Area (06) Enabling Technologies and it most directly relates to several Specific Challenge Topics involving Epigenetics, including the following: 06-DA-103 and 06-OD-105 "Identification of chemical modulators of epigenetic regulators"; 06-OD-108 "In vivo Epigenetic imaging reagents"; 08-AG-102 "Epigenetic changes - Identification of epigenetic changes that are specifically associated with age-related neurodegenerative diseases"; 03-DA-102* "Novel molecular targets from unexpected sources"; 03-AG-102 "Novel biomarkers for Alzheimer's disease"; 03-AG-103 "Biomarkers for neurodegenerative diseases"; 06-AG-105 "Tools facilitating chemistry and biology collaborations"; 03-HL-101* "Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction"; 06-HL-107 "Develop new technologies to advance heart, lung, and blood research." The proposed research uses a novel mechanism-based approach and has the potential to discover drugs and biomarkers for multiple diseases in the neuronal, immune and cardiovascular systems.

描述（由申请人提供）：对基因表达对许多生物学和医学领域的表观遗传调节的重要性的越来越多，导致对这一领域的兴趣日益增长。尽管有很多进展，但我们对表观遗传事件所涉及的分子方面的理解仍然缺乏，并且对新方法和新的分子工具的需求越来越不断增长，以实现该领域的未来进步。当前的大多数表观遗传调节剂的小分子调节剂通过与修饰染色质的酶的催化位点结合而起作用。由于催化位点通常由具有不同细胞作用的多种酶共享，因此在这一研究领域的主要挑战是缺乏可以针对特定酶的小分子，这将极大地促进表观遗传调节的基本机制，并可能导致更具体且有效的治疗疗法。本应用中提出的研究的长期目标是探索表观遗传调节剂的不同干预方式，即通过靶向其调节络合物中的蛋白质 - 蛋白质相互作用。具体而言，将开发小分子抑制剂，用于在T细胞，神经元和肌肉中高度表达组蛋白脱乙酰基酶（IIA HDACS）的亚类，并且是HDAC抑制剂的潜在靶标，它们在炎症，神经减退症的较小摩尔群中搜索了较小的摩尔群，该型在炎症中均显示出有益的效应使用MEF2/HDAC相互作用作为建立原理证明的一种方式，将HDAC与其功能转录因子合作伙伴伴侣。为了实现这一目标，两个主要研究者将依靠他们在结构生物学和合成/药物化学方面的丰富和互补经验来识别和利用该问题的相关分子方面，包括：有关现有HDAC抑制剂的大量功能数据，有关MEF2/HDAC Interication的详细生物化学和结构信息的可用性，以及u Ulivation的详细生物化学和结构信息。基本方法是结合基于结构的建模，靶向屏幕和结构功能验证，以搜索此类特定的HDAC抑制剂。使用这种方法，初步研究已经确定了这种类型的几种有希望的小分子抑制剂，这些抑制剂将进行详细研究。拟议的研究将进一步表征这些分子的功能和特性，并为开发用于研究HDAC功能的新分子探针的基础，包括成像剂和许多主要疾病的潜在治疗剂。总体而言，拟议的研究将作为解决调节络合物中蛋白质相互作用的可行性的一个例子，作为开发表观遗传调节剂化学调节剂的一种方法。 HDAC功能的新的小分子调节剂将被开发，预计将是特定于亚型的，并且应该有助于在越来越重要的表观遗传学领域及其在几种疾病领域的许多应用中取得多种进步。这些研究还将提供新的工具来研究关键靶基因，这些基因可以作为神经元，免疫和心血管系统疾病的生物标志物。基于机理的小分子表观遗传调节剂：靶向特定的HDAC 公共卫生相关性：该应用程序解决了广泛的挑战领域（06）促成技术，并且最直接地与涉及表观遗传学的几个特定挑战主题有关，包括以下内容：06-DA-103和06-OD-105“表观遗传调节剂化学调节剂的识别”； 06-OD-108“体内表观遗传成像试剂”； 08-ag-102“表观遗传变化 - 与年龄相关的神经退行性疾病特别相关的表观遗传变化的鉴定”； 03-DA-102*“来自意外来源的新分子靶标”； 03-AG-102“阿尔茨海默氏病的新型生物标志物”； 03-AG-103“神经退行性疾病的生物标志物”； 06-AG-105“促进化学和生物学合作的工具”； 03-HL-101*“识别并验证并验证对血液，血管，心脏和呼吸道功能障碍的诊断和治疗反应的临床相关，可量化的生物标志物”； 06-HL-107“开发新技术以促进心脏，肺和血液研究。”拟议的研究使用了一种新型的基于机制的方法，并有可能发现神经元，免疫和心血管系统中多种疾病的药物和生物标志物。