Chemical Biology of Caged Garcinia Xanthones

项目摘要 笼状山竹子的氧杂蒽酮具有独特的结构，强大的生物活性和很大程度上尚未开发 生物学行为模式。包括我们自己在内的几个实验室最近的研究结果表明， 这些分子在包括多药耐药克隆的几种癌细胞中诱导凋亡， 良好的治疗窗口在药物发现中的潜在应用。这些的作用方式 化合物被认为涉及与转铁蛋白受体（TfR）的结合，但结合位点和 这种结合在细胞信号传导中的结果还没有被研究。在这里，我们提出了一个 跨学科的研究计划，将解决有关的化学生物学的问题， 笼状山竹子我们建议确定这些分子的晶体结构， 与人TfR胞外域复合并鉴定其结合位点。此信息将用于 鉴定并优化其药效基序。我们将测量它们的结合常数， 化合物与TfR的关系，并将它们与它们的细胞毒性值相关联。我们还将评估是否具有约束力 小分子对TfR的影响影响TfR的内吞作用，并决定信号通路， 激活导致细胞凋亡。这项工作将为基于结构的药物设计提供新的信息 靶向转铁蛋白受体并产生关于转铁蛋白结构的基础知识 受体及其在细胞信号传导和凋亡中的作用。

Project Summary The caged Garcinia xanthones have unique structures, potent bioactivities and largely unexplored biological mode of action. Recent findings from several laboratories, including our own, have shown that these molecules induce apoptosis in several cancer cells including multidrug resistant clones and have a good therapeutic window for potential applications in drug discovery. The mode of action of these compounds is proposed to involve binding to the transferrin receptor (TfR) but the binding site and consequences of this binding in cell signaling have not been examined. Here we present an interdisciplinary research program that would address issues related to the chemical biology of the caged Garcinia xanthones. We propose to determine the crystal structure of these molecules in complex with the human TfR ectodomain and identify their binding site. This information will be used to identify and optimize their pharmacophoric motif. We will measure binding constants of these compounds to TfR and correlate them to their cytotoxicity values. We will also evaluate whether binding of the small molecules to TfR affects TfR endocytosis and determine signaling pathways that become activated leading to apoptosis. This work will produce new information for structure-based drug design targeting the transferrin receptor and generate fundamental knowledge on the structure of the transferrin receptor and its role in cell signaling and apoptosis.