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
基本信息
- 批准号:7832120
- 负责人:
- 金额:$ 50万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffinityAlzheimer&aposs DiseaseAreaBindingBinding SitesBiochemicalBiological MarkersBiologyBloodBlood VesselsCardiacCardiovascular systemCatalytic DomainChemicalsChemistryChromatinChromatin StructureCollaborationsComplexDNA BindingDataDevelopmentDiagnosticDiseaseDisease modelEnzymesEpigenetic ProcessEventFamilyFunctional disorderFutureGene ExpressionGene Expression RegulationGene TargetingGoalsHDAC4 geneHeartHeart HypertrophyHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHistonesImageImmuneIn VitroInflammationInhibitory Concentration 50InterventionLeadLungMalignant NeoplasmsMediatingMedicineMethodologyMethodsModelingMolecularMolecular ProbesMolecular TargetMuscleMuscle CellsNerve DegenerationNeurodegenerative DisordersNeuronsNew AgentsPharmaceutical ChemistryPharmaceutical PreparationsPrincipal InvestigatorPropertyProteinsReagentRegulationResearchRespiratory SystemRespiratory tract structureRoleSeriesSourceStructureT-LymphocyteTechnologyTherapeuticTherapeutic EffectValidationWorkZincage relatedbasecancer therapyclinically relevantdesigndrug developmentdrug discoveryexperiencehuman diseasein vivoinhibitor/antagonistinsightinterestmembermyocyte-specific enhancer-binding factor 2new technologynovelnovel strategiesprogramspromoterprotein protein interactionpublic health relevanceresponsesmall moleculestructural biologytooltranscription factor
项目摘要
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):人们越来越认识到基因表达的表观遗传调控对于生物学和医学众多领域的重要性,导致人们对该领域的兴趣日益浓厚。尽管取得了许多进展,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,并且对新方法和新分子工具的需求不断增长,以实现该领域的未来进步。目前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来发挥作用。由于催化位点通常由具有不同细胞作用的多种酶共享,该研究领域的一个主要挑战是缺乏可以靶向特定酶的小分子,这将极大地促进表观遗传调控基本机制的研究并可能导致更具体和有效的治疗方法。本申请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模式,即通过靶向其调节复合物中的蛋白质-蛋白质相互作用。具体来说,将为组蛋白脱乙酰酶的一个亚类(IIa 类 HDAC)开发小分子抑制剂,该亚类在 T 细胞、神经元和肌肉中高表达,是 HDAC 抑制剂的潜在靶标,在炎症、神经退行性疾病和心脏疾病方面显示出有益作用。该提案的总体策略是寻找能够阻断 IIa 类 HDAC 与其功能性转录因子伴侣结合的小分子,使用 MEF2/HDAC 相互作用作为建立原理证明的方法。为了实现这一目标,两位主要研究人员将依靠他们在结构生物学和合成/药物化学方面广泛且互补的经验来识别和利用该问题的相关分子方面,包括:现有 HDAC 抑制剂的大量功能数据、有关 MEF2/HDAC 相互作用的详细生化和结构信息,以及基于化学的新型方法的利用。基本方法是结合基于结构的建模、靶向筛选和结构功能验证来寻找此类亚类特异性 HDAC 抑制剂。使用这种方法,初步研究已经确定了几种有前途的此类小分子抑制剂,将对其进行详细研究。拟议的研究将进一步表征这些分子的功能和特性,并为开发新的分子探针来研究 HDAC 功能奠定基础,包括显像剂和用于许多主要疾病的潜在治疗的新先导化合物。总体而言,拟议的研究将作为一个例子来解决阻断调节复合物中蛋白质-蛋白质相互作用作为开发表观遗传调节剂化学调节剂的方法的可行性。即将开发的新的 HDAC 功能小分子调节剂预计将具有亚型特异性,并应有助于在日益重要且仍在新兴的表观遗传学领域取得多项进展,及其在多个疾病领域的许多应用。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。基于机制的小分子表观遗传调节剂:针对特定 HDAC
公共健康相关性:本申请解决了广泛的挑战领域 (06) 使能技术,它与涉及表观遗传学的几个具体挑战主题最直接相关,包括以下内容:06-DA-103 和 06-OD-105“表观遗传学化学调节剂的识别”监管机构”; 06-OD-108“体内表观遗传成像试剂”; 08-AG-102“表观遗传变化 - 鉴定与年龄相关的神经退行性疾病特别相关的表观遗传变化”; 03-DA-102*“来自意想不到来源的新分子靶标”; 03-AG-102“阿尔茨海默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*“识别和验证血液、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“开发新技术以推进心脏、肺和血液研究。”拟议的研究采用了一种新颖的基于机制的方法,有可能发现神经元、免疫和心血管系统多种疾病的药物和生物标志物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)
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