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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：
8660675
负责人：
Michael Ohlmeyer
金额：
$ 42.19万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660675
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 Gene Expression Profile Genes Genetic Transcription Goals Half-Life Histone Acetylation Histone H3 Histones 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 Series Specificity Staging Stimulus Structure Synthesis Chemistry 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 response scaffold scale up screening small molecule small molecule libraries social stimulant abuse tool transcription factor

项目摘要

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 ¿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 dependant on CBP (CREB binding protein) dependant histone acetyl transferase (HAT) activity. Thus exposure to drugs of abuse 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, ¿FosB, is expressed and this accumulates in neurons as the transition to an addicted state occurs. ¿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 ¿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 ¿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.

成瘾是一种慢性、复发性精神障碍，其特征是强迫性药物寻求尽管对相关个人造成了重大的身体、精神和社会伤害，但仍存在这些行为。进展已经阐明了成瘾中发生的潜在神经适应。其中包括，在某种程度上，这是一种对正常神经元可塑性的颠覆或劫持，学习细胞对外部刺激的反应方式之一，包括病理性刺激，如滥用精神兴奋剂，是通过改变他们的基因表达模式，是通过表观遗传变化导致基因转录模式的改变。感应<$FosB是一个很好的与这些药物长期给药相关的特征性神经可塑性事件。暴露于滥用的精神兴奋剂，如可卡因，导致基因组蛋白乙酰化启动子和随后的转录激活早期反应基因，包括FosB。 FosB启动子乙酰化的增加已显示依赖于CBP（CREB结合蛋白）依赖性组蛋白乙酰转移酶（HAT）活性。因此，暴露于滥用药物，可卡因和安非他明已被证明会导致FosB蛋白在细胞中的表达增加，脑桥核在长期治疗中，一种寿命更长的FosB截短剪接变体， FosB的表达，并积累在神经元作为过渡到一个上瘾的状态发生。药物停药后，FosB存在的时间延长，因此，在长期成瘾行为的形成中作为一种致病因素，复发倾向拟议研究要检验的关键生物学假设是小分子抑制剂对CBP活性的减弱将减少 FosB基因启动子，这反过来又会降低FosB和<$FosB蛋白的表达。西奈山化学库的高通量筛选已经确定了两个系列的命中分子与CBP布罗莫结构域的结合测定。此外，这些命中已被证明抑制在基于细胞的报告基因测定中CBP介导的HAT活性。这些化学铅系涉及通过平行合成技术进行探索和精细化以创建CBP抑制剂文库。该提案的广泛主题是通过靶向文库合成优化这些命中，药物化学，以提供小分子，这将抑制FosB诱导，通过 CBP HAT活性减弱。这些小分子将作为药理学工具，研究过渡到成瘾状态的潜在神经适应，并可能提供一个用于预防或逆转成瘾的新的治疗方式。