Small molecule probes of cytokinesis

胞质分裂的小分子探针

基本信息

批准号：
8020047
负责人：
ULRIKE S EGGERT
金额：
$ 38.97万
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/8020047
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.

描述（由申请人提供）：细胞如何调节和执行胞质分裂（细胞分裂的最后一步）仍然是基础生物学中未解决的主要问题之一。我们的长期目标是系统地剖析胞质分裂过程中的时间和空间控制。用传统方法研究胞质分裂一直具有挑战性，因为它是一个快速过程，并且许多关键的胞质分裂蛋白也在细胞周期的早期发挥重要功能。这就是为什么作用迅速且具有高度时间控制能力的小分子是研究胞质分裂的理想工具。我们发现并表征了几种新型的胞质分裂小分子抑制剂。使用这些小分子作为工具，我们现在可以解决胞质分裂研究中的一些重要的悬而未决的问题。例如，肌动蛋白如何组装成可收缩的环结构以及环如何收缩？胞质分裂是如何在详细和更全面的水平上进行调节的？基于有趣的初步表征，我们选择了三种具有不同抑制机制的小分子进行进一步分析。其中一种小分子导致肌动蛋白丝聚集，但不与肌动蛋白本身结合，一种以 Aurora B 激酶信号通路为目标，并使 Aurora B 复合蛋白 INCENP 错误定位，第三种是哺乳动物细胞中胞质分裂的有效抑制剂。为了充分发挥这些有前途的小分子的潜力，我们建议确定它们的细胞靶标。我们设计了一种跨学科的方法，结合化学、成像技术和生物化学，利用小分子来探讨胞质分裂机制的不同方面。除了作为有用的工具化合物外，我们的胞质分裂小分子抑制剂还可以催化治疗性癌症药物的开发。