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:
- 金额:$ 42.19万
- 依托单位:
- 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:
- 关键词:AcetylationAcuteAddictive BehaviorAddressAffinityAmphetaminesAnimalsAreaAttenuatedBackBehavioralBehavioral ModelBindingBiologicalBiological AssayBiological AvailabilityBrainBromodomainCREB-binding proteinCell NucleusCellsChemicalsChronicCocaineComplexComputational TechniqueDatabasesDoseDrug AddictionERG geneEpigenetic ProcessEvaluationEventExposure toFluorescenceFluorescence SpectroscopyGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGoalsHalf-LifeHistone AcetylationHistone H3HistonesIn VitroIndividualInhibitory Concentration 50InvestigationLabelLeadLearningLibrariesLifeLigand BindingLigandsLinkLuciferasesLysineMeasuresMediatingMemoryMental disordersMethodsMethylationModalityModelingMolecular ModelsNeuronal PlasticityNeuronsNucleus AccumbensOralParentsPatternPenetrationPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePhosphorylationPreparationPreventionProcessPropertyPsyche structureRNA SplicingRattusReagentRecruitment ActivityRelapseReporterResearchRewardsRodent ModelRoentgen RaysRoleRouteRunningSafetySeriesSpecificityStagingStimulusStructureSynthesis ChemistrySystemTechniquesTestingTimeTranscriptional ActivationTransferaseTryptophanUbiquitinationVariantaddictionattenuationbasedesigndrug of abusedrug seeking behaviorhigh throughput screeninghuman CREBBP proteinin vivoinhibitor/antagonistinsightlead seriesmolecular modelingnovelnovel therapeuticsprogramspromoterprotein expressionprotein functionresponsescaffoldscale upscreeningsmall moleculesmall molecule librariessocialstimulant abusetooltranscription 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Ohlmeyer其他文献
Michael Ohlmeyer的其他文献
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{{ truncateString('Michael Ohlmeyer', 18)}}的其他基金
Direct Activation of PP2A as a Novel Approach to Group-3 Medulloblastoma Therapy
直接激活 PP2A 作为 3 组髓母细胞瘤治疗的新方法
- 批准号:
10382481 - 财政年份:2022
- 资助金额:
$ 42.19万 - 项目类别:
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:
8507692 - 财政年份:2010
- 资助金额:
$ 42.19万 - 项目类别:
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:
8484932 - 财政年份:2010
- 资助金额:
$ 42.19万 - 项目类别:
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:
7998834 - 财政年份:2010
- 资助金额:
$ 42.19万 - 项目类别:
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:
8119022 - 财政年份:2010
- 资助金额:
$ 42.19万 - 项目类别:
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