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，复发的精神疾病，其特征是强迫毒品寻求行为，尽管对所涉及的个人有严重的身体，心理和社会伤害。在阐明成瘾中发生的基本神经适应的过程中取得了进展。这些部分涉及正常神经可塑性相关的奖励，记忆和学习的颠覆或劫持。细胞对外部刺激的反应之一，包括病理刺激，例如滥用精神刺激物，是改变其基因表达模式，一种机制是通过表观遗传变化导致基因转录模式改变的。诱导Delta FOSB是与这些药物长期给药有关的一个特征性的神经塑性事件。暴露于滥用的肺泡剂，例如可卡因，导致基因启动子的组蛋白乙酰化，以及随之而来的早期反应基因的转录激活，包括FOSB。 FOSB启动子乙酰化的增加已被证明取决于CBP（CREB结合蛋白）依赖性组蛋白乙酰转移酶（HAT）活性。因此，已证明可卡因和苯丙胺这种滥用药物会导致伏隔核细胞中的FOSB蛋白表达增加。在慢性治疗中，表达了FOSB，Delta FOSB的更长的截短剪接变体，并且随着到上瘾状态的过渡发生时，这种变体在神经元中积聚。在撤回药物后，Delta FOSB长期存在，因此在形成长期成瘾行为的形成中，它被认为是一种致命剂，因此倾向于复发。拟议的研究要检验的关键生物学假设是，小分子抑制剂对CBP活性的衰减将减少FOSB基因启动子的乙酰化，这反过来又将降低FOSB和Delta FOSB蛋白的表达。西奈山的化学文库的高吞吐量筛选已经确定了与CBP溴结构域结合测定中的两个系列HIT分子。此外，这些命中已被证明可以抑制基于细胞的记者测定中CBP介导的HAT活性。这些化学铅系列可以通过平行合成技术来探索和阐述，以创建CBP抑制剂库。该提案的广泛主题是通过有针对性的文库合成和药物化学来优化这些命中，以提供小分子，这些分子将通过衰减CBP HAT活性来抑制Delta FOSB诱导。这些小分子将充当药理工具，以研究过渡到上瘾状态的潜在神经元适应，并可能为预防或逆转成瘾提供一种新颖的治疗方式。公共卫生相关性：成瘾是一种慢性，复发的精神疾病，其特征是强迫性毒品寻求行为。成瘾中涉及的神经元变化部分表观遗传学，导致颠覆或劫持正常的神经元可塑性相关的奖励，记忆和学习机制。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；这些小分子将充当药理学工具，以研究过渡到上瘾状态的潜在神经元过程，并可能为预防或逆转成瘾提供一种新型的治疗方式。