Small molecule probes of cytokinesis

胞质分裂的小分子探针

基本信息

批准号：
8017189
负责人：
ULRIKE S EGGERT
金额：
$ 43.31万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8017189
关键词：
Actin-Binding Protein Actins Active Sites Address Adrenergic Receptor Adverse drug effect Affect Affinity Chromatography Antihypertensive Agents Antineoplastic Agents Binding Biochemical Biochemistry Biological Assay Biological Factors Biology Biotin Cell Cycle Cell Surface Receptors Cell division Cell surface Cells Chemicals Chemistry Clinical Complex Cultured Cells Cytokinesis Data Dextrans Disease Dissection Drosophila genus Drug Delivery Systems Goals Human Image Imaging Techniques Label Lead Life Link Malignant Neoplasms Mammalian Cell Methods Microfilaments Mitosis Modeling Morphogenesis Pathway interactions Pattern Permeability Pharmaceutical Preparations Phosphorylation Phosphotransferases Prazosin Process Proteins Proteomics RNA Interference Regulation Research Role Screening procedure Signal Pathway Spatial Distribution Structure Testing Therapeutic Work aurora B kinase aurora kinase base borealin cell cortex cellular imaging cellular targeting design dextran genome-wide inhibitor/antagonist inner centromere protein interdisciplinary approach kinase inhibitor novel novel therapeutics protein complex research study small molecule survivin therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): How cells regulate and execute cytokinesis, the final step in cell division, remains one of the major unsolved questions in basic biology. Our long-term goal is the systematic dissection of temporal and spatial control during cytokinesis. It has been challenging to study cytokinesis with traditional methods because it is a rapid process and many key cytokinesis proteins also perform important functions earlier in the cell cycle. This is why small molecules, which act rapidly and with high temporal control, are ideal tools to study cytokinesis. We discovered and characterized several novel small molecule inhibitors of cytokinesis. Using these small molecules as tools, we can now address some important outstanding questions in cytokinesis research. For example, how is actin assembled into a contractile ring structure and how does the ring constrict? How is cytokinesis regulated, both at a detailed and more global level? Based on intriguing preliminary characterizations, we selected three small molecules with different mechanisms of inhibition for further analysis. One of these small molecules causes the aggregation of actin filaments without binding actin itself, one targets the Aurora B kinase signaling pathway and mis-localizes the Aurora B complex protein INCENP and the third is a potent inhibitor of cytokinesis in mammalian cells. To realize the full potential of these promising small molecules, we propose to identify their cellular targets. We have designed an interdisciplinary approach, combining chemistry, imaging techniques and biochemistry to use the small molecules to probe different aspects of the mechanism of cytokinesis. In addition to being useful tool compounds, our small molecule inhibitors of cytokinesis may also catalyze the development of therapeutic cancer drugs. Many mechanisms underlying cytokinesis, the final step in cell division, remain poorly understood. Failed cell division is causal or contributory in diseases such as cancer. Small molecules that specifically target cytokinesis, the subject of this proposal, are important tools to study the underlying biology of cell division and could catalyze the discovery of therapeutic drugs to treat cancer.

描述（由申请人提供）：细胞如何调节和执行细胞因子（细胞分裂的最后一步）仍然是基本生物学的主要未解决问题之一。我们的长期目标是细胞因子期间时间和空间控制的系统解剖。使用传统方法研究细胞因子是一个挑战，因为这是一个快速过程，许多关键的细胞因子蛋白在细胞周期早期也执行重要功能。这就是为什么迅速起作用并具有高时间控制的小分子是研究细胞因子的理想工具。我们发现并表征了几种新型细胞因子的小分子抑制剂。现在，我们可以将这些小分子作为工具，现在可以解决细胞动力研究中的一些重要问题。例如，肌动蛋白如何组装成收缩环结构，环如何收缩？在详细和更全球的水平上，细胞因子如何调节细胞因子？基于有趣的初步特征，我们选择了三个具有不同机制抑制机制的小分子进行进一步分析。这些小分子之一导致肌动蛋白丝的聚集而没有结合肌动蛋白本身，一个人靶向极光B激酶信号传导途径，并将其定位于Aurora B复合物蛋白incenp，而第三个是哺乳动物细胞中细胞因子的有效抑制剂。为了实现这些有希望的小分子的全部潜力，我们建议鉴定它们的细胞靶标。我们设计了一种跨学科方法，结合了化学，成像技术和生物化学，以使用小分子来探测细胞因子机制的不同方面。除了成为有用的工具化合物外，我们的小分子抑制剂还可能催化治疗性癌症药物的发展。细胞因子的基本机制，即细胞分裂的最后一步，仍然了解不足。失败的细胞分裂是癌症等疾病的因果关系。该提案的主题是专门针对细胞因子的小分子，是研究细胞分裂的潜在生物学的重要工具，并可能催化发现治疗药物以治疗癌症。