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

• 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
• 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

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严重的身体、精神和社会伤害，但仍采取行为。进步 已被用来阐明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。细胞响应外部刺激的方式之一，包括病理刺激，例如 滥用精神兴奋剂，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改变。感应 ¿FosB 是一个井 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，接触滥用药物，例如 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 伏隔核。在长期治疗中，FosB 的寿命较长的截短剪接变体， 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 复发倾向。本研究要检验的关键生物学假设是 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 蛋白的表达。 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 分子与 CBP 溴结构域的结合测定。此外，这些打击已被证明可以抑制 CBP 在基于细胞的报告基因检测中介导 HAT 活性。这些化学铅系列是可以接受的 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 药物化学提供小分子，通过抑制 ¿FosB 诱导 CBP HAT 活性减弱。这些小分子将作为药理学工具 研究向成瘾状态过渡的潜在神经元适应，并可能提供 预防或逆转成瘾的新治疗方式。