Small Molecule Libraries Targeted to CBP and Attenuation AfosB Expression

描述（由申请人提供）：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行为，尽管对所涉及的个人造成了重大的身体、精神和社会伤害。在阐明成瘾中发生的潜在神经适应方面已经取得了进展。这些部分涉及颠覆或劫持与奖励，记忆和学习相关的正常神经元可塑性。细胞对外部刺激（包括滥用精神兴奋剂等病理刺激）的反应方式之一是改变其基因表达模式，其机制之一是通过表观遗传变化导致基因转录模式改变。诱导δ FosB是一种与这些药物长期给药相关的充分表征的神经可塑性事件。暴露于滥用的精神兴奋剂，例如可卡因，导致基因启动子的组蛋白乙酰化，以及随后的早期反应基因（包括FosB）的转录激活。已显示FosB启动子乙酰化的增加依赖于CBP（CREB结合蛋白）依赖性组蛋白乙酰转移酶（HAT）活性。因此，暴露于滥用的药物如可卡因和安非他明已被证明会导致增加FosB蛋白表达的细胞的核。在慢性治疗中，FosB的更长寿命的截短剪接变体Δ FosB被表达，并且随着向成瘾状态的转变发生，这在神经元中积累。Delta FosB在停药后存在较长时间，因此它被认为是形成长期成瘾行为的致病因子，因此有复发倾向。拟议研究要检验的关键生物学假设是，小分子抑制剂减弱CBP活性将减少FosB基因启动子的乙酰化，这反过来又会降低FosB和Δ FosB蛋白的表达。在西奈山的化学文库的高通量筛选已经在与CBP溴结构域的结合测定中鉴定了两个系列的命中分子。此外，在基于细胞的报告基因测定中，这些命中已显示出抑制CBP介导的HAT活性。这些化学先导系列适合于通过平行合成技术进行探索和精细化，以创建CBP抑制剂库。该提案的广泛主题是通过靶向文库合成和药物化学优化这些命中，以提供将通过减弱CBP HAT活性来抑制Δ FosB诱导的小分子。这些小分子将作为药理学工具，以调查潜在的神经元适应过渡到成瘾状态，并可能提供一种新的治疗模式，用于预防或逆转成瘾。 公共卫生相关性：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行为。成瘾中涉及的神经元变化部分是表观遗传的，并导致大脑中与奖励、记忆和学习机制相关的正常神经元可塑性的颠覆或劫持。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;这些小分子将作为药理学工具来研究向成瘾状态过渡的潜在神经元过程，并可能为预防或逆转成瘾提供新的治疗方式。

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.