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

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

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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.

成瘾是一种长期复发的精神疾病，其特征是寻求强迫性药物行为目的地对所涉及的个人产生重大的身体，心理和社会伤害。进步已经阐明成瘾中发生的基本神经适应。这些涉及，在某种程度上，颠覆或劫持了正常神经可塑性相关的奖励，记忆和学习。细胞对外部刺激反应的方式之一，包括病理刺激，例如滥用的心理刺激物是通过改变其基因表达模式和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»FOSB是一口井与这些药物的长期给药有关的神经塑性事件的表征。暴露于滥用的术发生剂，例如可卡因，导致基因组蛋白乙酰化启动子以及随之而来的转录激活，包括早期反应基因，包括FOSB。 FOSB启动子乙酰化的增加已被证明取决于CBP（CREB结合蛋白质）依赖性组蛋白乙酰转移酶（HAT）活性。暴露于这样的滥用药物可卡因和苯丙胺已被证明会导致增加FOSB蛋白在细胞中的表达伏隔核。在慢性治疗中，FOSB的持续截断剪接变体更长 «fosb表示，随着到上瘾状态的过渡发生，这会在神经元中积聚。 �FOSB存在在撤回药物后很长一段时间，因此在形成长期添加剂行为的形成中，作为因果剂实施缓解的倾向。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，反过来将降低FOSB和FOSB蛋白的表达。西奈山的化学图书馆的高吞吐量屏幕已确定了两组命中与CBP溴结构域结合测定中的分子。此外，这些命中已被证明抑制 CBP介导的HAT活性在基于细胞的记者测定中。这些化学铅系列可正常通过平行合成技术探索和阐述，以创建CBP抑制剂库。该提案的广泛主题是通过针对性的库合成和提供小分子的药物化学，可以通过 CBP帽子活动的衰减。这些小分子将充当药品工具调查过渡到上瘾状态的潜在神经元适应，并可能提供预防或逆转成瘾的新型热模态。