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，复发性精神疾病，其特征是强迫性药物寻求行为，尽管对相关个体造成了重大的身体，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。在某种程度上，这涉及到与奖励、记忆和学习相关的正常神经元可塑性的颠覆或劫持。细胞对外部刺激的反应方式之一，包括病理刺激，如滥用精神兴奋剂，是通过改变它们的基因表达模式，其中一种机制是通过表观遗传改变导致基因转录模式的改变。诱导型δ FosB是与这些药物的长期使用相关的一种特征明确的神经可塑性事件。暴露于滥用的精神兴奋剂，例如可卡因，会导致基因启动子的组蛋白乙酰化，并导致包括FosB在内的早期反应基因的转录激活。FosB启动子乙酰化的增加已被证明依赖于CBP （CREB结合蛋白）依赖的组蛋白乙酰转移酶（HAT）活性。因此，暴露于可卡因和安非他明等滥用药物已被证明可导致伏隔核细胞中FosB蛋白表达增加。在慢性治疗中，长寿命的截断的FosB剪接变体，δ FosB，被表达，并在神经元中积累，过渡到成瘾状态发生。Delta FosB在停药后会持续很长一段时间，因此它被认为是形成长期成瘾行为和复发倾向的致病因子。本研究要验证的关键生物学假设是，小分子抑制剂抑制CBP活性会降低FosB基因启动子的乙酰化，从而降低FosB和δ FosB蛋白的表达。西奈山化学文库的高通量筛选已经在CBP溴域结合试验中确定了两个系列的命中分子。此外，在基于细胞的报告细胞试验中，这些命中已被证明可以抑制CBP介导的HAT活性。这些化学铅系列可以通过平行合成技术进行探索和完善，以创建CBP抑制剂文库。该提案的主要主题是通过靶向文库合成和药物化学来优化这些命中点，以提供通过衰减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来研究过渡到成瘾状态的潜在神经元适应，并可能为预防或逆转成瘾提供一种新的治疗方式。

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 Delta FosB is present for an extended period of time after drug is withdrawn and it has thus been implicated as a causative agent in the formation of longer term addictive behaviors and hence propensity for relapse.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.