Small Molecule Libraries Targeted to CBP and Attenuation AfosB Expression

靶向 CBP 和减弱 AfosB 表达的小分子文库

基本信息

批准号：
7998834
负责人：
Michael Ohlmeyer
金额：
$ 38.14万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7998834
关键词：
Acetylation Acute Addictive Behavior Address Affinity Amphetamines Animals Area Attenuated Back Behavioral Behavioral Model Binding Biological Biological Assay Biological Availability Brain Bromodomain CREB-binding protein Cell Nucleus Cells Chemicals Chronic Cocaine Complex Computational Technique Databases Dose Drug Addiction ERG gene Epigenetic Process Evaluation Event Exposure to Fluorescence Fluorescence Spectroscopy Gene Expression Genes Genetic Transcription Goals Half-Life Histone Acetylation Histone H3 Histones Humulus In Vitro Individual Inhibitory Concentration 50 Investigation Label Lead Learning Libraries Life Ligand Binding Ligands Link Luciferases Lysine Measures Mediating Memory Mental disorders Methods Methylation Modality Modeling Molecular Models Neuronal Plasticity Neurons Nucleus Accumbens Oral Parents Pattern Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phosphorylation Preparation Prevention Process Property Psyche structure RNA Splicing Rattus Reagent Recruitment Activity Relapse Reporter Research Rewards Rodent Model Roentgen Rays Role Route Running Safety Screening procedure Series Specificity Staging Stimulus Structure System Techniques Testing Time Transcriptional Activation Transferase Tryptophan Ubiquitination Variant addiction attenuation base design drug of abuse drug seeking behavior high throughput screening human CREBBP protein in vivo inhibitor/antagonist insight lead series molecular modeling novel novel therapeutics programs promoter protein expression protein function public health relevance response scaffold scale up small molecule small molecule libraries social stimulant abuse tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors despite significant physical, mental and social harm to the individuals involved. Progress has been made in elucidating the underlying neuroadaptions that occur in addiction. These involve, in part, a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning. One of the ways cells respond to external stimuli, including pathological stimuli such as abused psychostimulants, is by altering their pattern of gene expression and one mechanism for this is via epigenetic changes leading to altered patterns of gene transcription. Induction delta FosB is a well characterized neuroplastic event associated with chronic administration of these drugs. Exposure to abused psycostimulants, for example cocaine, leads to histone acetylation of gene promoters, and consequent transcriptional activation, of early response genes, including FosB. Increase in FosB promoter acetylation has been shown to be dependent on CBP (CREB binding protein) dependant histone acetyl transferase (HAT) activity. Thus exposure to drugs of abuses such cocaine and amphetamines have been shown to lead to increase FosB protein expression in cells of the nucleus accumbens. On chronic treatment, a longer lived truncated splice variant of FosB, delta FosB, is expressed and this accumulates in neurons as the transition to an addicted state occurs. Delta FosB is present for an extended period of time after drug is withdrawn and it has thus been implicated as a causative agent in the formation of longer term addictive behaviors and hence propensity for relapse. The key biological hypothesis to be tested by the proposed research is that attenuation of CBP activity by a small molecule inhibitor will reduce acetylation of the FosB gene promoter, which in turn will lower FosB and delta FosB protein expression. High throughput screens of chemical libraries at Mount Sinai have identified two series of hit molecules in a binding assay to CBP bromodomain. Further, these hits have been shown to inhibit CBP mediated HAT activity in cell based reporter assays. These chemical lead series are amenable to exploration and elaboration by parallel synthesis techniques to create libraries of CBP inhibitors. The broad theme of this proposal is to optimize these hits via targeted library synthesis and medicinal chemistry to provide small molecules which will inhibit delta FosB induction via attenuation of CBP HAT activity. These small molecules will function as pharmacological tools to investigate the underlying neuronal adaptations in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction. PUBLIC HEALTH RELEVANCE: Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors. Neuronal changes involved in addiction are partly epigenetic and result in a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning mechanisms in the brain. The theme of this proposal is to identify and optimize small molecules that modulate and attenuate the epigenetic processes associated with addiction; these small molecules will function as pharmacological tools to investigate the underlying neuronal processes in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction.

描述（由申请人提供）：成瘾是一种慢性、复发性精神疾病，其特征是强迫性寻求药物行为，尽管对相关个人造成了严重的身体、精神和社会伤害。在阐明成瘾中发生的潜在神经适应方面已经取得了进展。这些在一定程度上涉及对与奖励、记忆和学习相关的正常神经元可塑性的颠覆或劫持。细胞对外部刺激（包括滥用精神兴奋剂等病理刺激）作出反应的方式之一是改变其基因表达模式，其机制之一是通过表观遗传变化导致基因转录模式改变。诱导 delta FosB 是一种与长期服用这些药物相关的明确特征的神经塑性事件。接触滥用的精神兴奋剂（例如可卡因）会导致基因启动子的组蛋白乙酰化，以及随后的早期反应基因（包括 FosB）的转录激活。 FosB 启动子乙酰化的增加已被证明依赖于 CBP（CREB 结合蛋白）依赖的组蛋白乙酰转移酶 (HAT) 活性。因此，接触可卡因和安非他明等滥用药物已被证明会导致伏隔核细胞中 FosB 蛋白表达增加。在长期治疗中，会表达一种寿命较长的 FosB 截短剪接变体，即 delta FosB，并且随着向成瘾状态的转变发生，这种变体会在神经元中积累。停药后，Delta FosB 会存在很长一段时间，因此它被认为是长期成瘾行为形成和复发倾向的致病因素。这项研究要测试的关键生物学假设是，小分子抑制剂减弱 CBP 活性将减少 FosB 基因启动子的乙酰化，进而降低 FosB 和 delta FosB 蛋白的表达。西奈山化学库的高通量筛选在与 CBP 溴结构域的结合测定中鉴定出了两个系列的命中分子。此外，在基于细胞的报告基因测定中，这些命中已被证明可以抑制 CBP 介导的 HAT 活性。这些先导化合物系列适合通过平行合成技术进行探索和阐述，以创建 CBP 抑制剂库。该提案的主要主题是通过靶向文库合成和药物化学来优化这些命中，以提供通过减弱 CBP HAT 活性来抑制 delta FosB 诱导的小分子。这些小分子将作为药理学工具来研究向成瘾状态过渡的潜在神经元适应，并可能为预防或逆转成瘾提供一种新的治疗方式。公共卫生相关性：成瘾是一种慢性、复发性精神疾病，其特征是强迫性寻求药物行为。成瘾所涉及的神经元变化部分是表观遗传的，并导致大脑中与奖励、记忆和学习机制相关的正常神经元可塑性的颠覆或劫持。该提案的主题是识别和优化调节和减弱与成瘾相关的表观遗传过程的小分子；这些小分子将作为药理学工具来研究向成瘾状态过渡的潜在神经元过程，并可能为预防或逆转成瘾提供一种新的治疗方式。