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：
8507692
负责人：
Michael Ohlmeyer
金额：
$ 40.5万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507692
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 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 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、复发性精神疾病，其特征是强迫性寻求药物尽管对相关个人造成了严重的身体、精神和社会伤害，但行为仍然取得进展。已经阐明了成瘾中发生的潜在神经适应，这些涉及，在某种程度上，颠覆或劫持了与奖励、记忆和神经元相关的正常神经元可塑性。学习是细胞响应外部刺激的方式之一，包括病理刺激，例如精神滥用兴奋剂是通过改变其基因表达模式及其一种机制是通过表观遗传变化导致基因转录模式的改变。 FosB 是一口井与长期服用这些药物相关的特征性神经塑性事件。接触滥用的精神兴奋剂，例如可卡因，会导致基因组蛋白乙酰化早期反应基因（包括 FosB）的启动子以及随后的转录激活。 FosB 启动子乙酰化的增加已被证明依赖于 CBP（CREB 结合蛋白质）依赖的组蛋白乙酰转移酶（HAT）活性因此暴露于滥用药物等。可卡因和安非他明已被证明会导致细胞中 FosB 蛋白表达增加在长期治疗中，FosB 的寿命更长的截短剪接变体， ¿ FosB 被表达，并且随着向成瘾状态的转变发生，它在神经元中积累。 ¿ FosB 在停药后仍存在很长一段时间，因此已被作为长期成瘾行为形成的致病因素，因此本研究要测试的关键生物学假设是复发倾向。小分子抑制剂减弱 CBP 活性将减少 CBP 的乙酰化 FosB 基因启动子，反过来会降低 FosB 和 ¿ FosB 蛋白表达。西奈山化学库的高通量筛选已确定了两个系列的热门产品此外，这些分子已被证明可以抑制 CBP 溴结构域的结合。 CBP 介导的 HAT 活性适用于基于细胞的报告基因检测。通过平行合成技术探索和阐述以创建 CBP 抑制剂库。该提案的主要主题是通过目标库合成和优化这些命中药物化学提供抑制的小分子 ¿ FosB 诱导通过 CBP HAT 活性的减弱这些小分子将起到药理学工具的作用。研究向成瘾状态过渡的潜在神经适应，并可能提供预防或逆转成瘾的新治疗方式。