Identification of Small Molecule Ligands with NGF Potentiating Activity

描述(申请人提供)：本申请中描述的研究的具体目标是开发新的有效和选择性的神经生长因子依赖活性的小分子增强剂，并从新的途径和细胞靶点方面表征它们促进神经元分化和存活的作用机制。长期的目标是开发宝贵的工具，以更好地了解活动增强的一般机制和NGF在促进神经过程发展中的作用。识别出的具有可接受治疗特征的导联将在SAR中取得进展，最终目标是开发治疗药物，防止或延缓由启动和维持轴突延伸的分子和化学线索缺陷引起的神经变性的开始。这项研究将利用化学信息学和HTS的方法来鉴定具有核心化学支架的新结构和分子，这些结构和分子类似于来自小分子化学库的天然产物的NGF依赖的轴突延伸的已知增强子。活性化合物将在神经细胞谱系中以效力、有效性、选择性和特异性来表征，以识别先导化合物。将启动对铅化合物作用机制的研究，以建立与已确定的铅相互作用的新途径和细胞靶标。具有治疗价值的NGF增强剂的成功开发将对改变与年龄相关的神经退行性疾病和其他痴呆的结局产生巨大影响。

DESCRIPTION (provided by applicant): The specific aims of the research described in this application are to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action in promoting neuronal differentiation and survival with regard to new pathways and cellular targets. The objectives in the long term are to develop invaluable tools to better understand the general mechanisms of activity potentiation and the roles of NGF in fostering the development of neural processes. Identified leads with acceptable therapeutic profiles will progress through SAR with the ultimate goal to develop therapeutic agents that prevent or delay the onset of neurodegeneration caused by defects in molecular and chemical cues that initiate and sustain neurite extension. This research will utilize the approaches of chemo-informatics and HTS to identify novel structures and molecules with core chemical scaffolds that are similar to known potentiators of NGF-dependent neurite extension of natural products origin from a chemical library of small molecules. Active compounds will be characterized for potency, efficacy, selectivity, and specificity in neuronal cell lineages to identify lead compounds. Studies on the mechanism of action of lead compounds will be initiated to establish novel pathways and cellular targets that interact with identified leads. Successful development of NGF potentiators with therapeutic values will have a tremendous impact in modifying the outcome of age-related neurodegenerative diseases and other dementias.