DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITORS OF AURORA B KINASE SIGNALING

新型 AURORA B 激酶信号传导小分子抑制剂的开发

• 批准号: 8359753
• 负责人: Charles Bradley Shuster
• 金额: $ 10.74万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359753
• 关键词: Anaphase; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Biomedical Research; Catalytic Domain; Cell division; Cells; Chemicals; Chromosome Segregation; Clinical; Clinical Trials; Collaborations; Complex; Cytokinesis; Development; Flow Cytometry; Funding; Grant; In Vitro; Intervention; Laboratories; Maintenance; Mitosis; Mitotic spindle; Molecular Bank; National Center for Research Resources; New Mexico; Play; Ploidies; Principal Investigator; Proteins; Reagent; Research; Research Infrastructure; Resources; Role; Screening procedure; Signal Transduction; Sister Chromatid; Source; Specificity; Structure; Translating; United States National Institutes of Health; Wit; aurora B kinase; base; clinical application; cost; in vivo; inhibitor/antagonist; inner centromere protein; novel; research study; scaffold; small molecule; small molecule libraries

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Maintenance of chromosomal ploidy during cell division requires a precise coordination of chromosome segregation and cytokinesis such that the cleavage does not occur before all replicated sister chromatids are correctly attached to the mitotic spindle and anaphase has been initiated. A conserved multi-subunit factor termed the Chromosomal Passenger Complex (CPC) plays a central role in coordinating mitosis and cytokinesis through its functions at the kinetechore early in mitosis and at the spindle midzone during cytokinesis. Its essential role in cell division have made the catalytic subunit of the CPC, Aurora B kinase, an attractive chemotherapeutic target, and there are currently several Aurora inhibitors in clinical trials. These inhibitors target the highly conserved ATP-binding site and consequentially display only limited specificity, thus restricting their applicability for both research- and clinical applications. In contrast to the highly conserved catalytic site, the interaction between Aurora B and its activating scaffold, INCENP, is unique to these two proteins and represents a potential- but unexploited target for intervention. In this application we will take advantage of reagents and assays developed in the laboratory to screen for novel, allosteric disrupters of Aurora B activity for use as probes for research and clinical applications. The lines of experimentation that form the Specific Aims of this proposal will: 1) develop a high-=throughput, flow-cytometry-based screen to identify candidate small molecules that disrupt Aurora B/INCENP interations; and 2) apply a chemical biological approach to optimize the efficacy of these molecules both in vitro and in vivo. These experiments will be performed in collaboration wit the NM-INBre Chemical Biology & Screen Collaborative Core (CBSC), and the UNM Molecular Libraries Screening Center, where high-throughput flow cytometry has been developed for biochemical- and cell-based screening of chemical libraries. From these studies, it is anticipated that not only will novel reagents be developed for the study of cell division, but that these reagents will potentially translate into the clinical arena, where targeting of this critical structure represents an excellent target for chemotherapeutic intervention.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在细胞分裂过程中维持染色体倍性需要精确的染色体分离和细胞因子的协调，以至于在将所有复制的姐妹染色质被正确连接到有丝分裂纺锤体和后期之前，裂解不会发生。称为染色体乘客复合物（CPC）的保守多亚基因子通过在有丝分裂的早期和细胞因子过程中的脊柱中Zone的功能中通过其在动力学上的动力学上的功能来协调有丝分裂和细胞因子的核心作用。它在细胞分裂中的重要作用使CPC的催化亚基，Aurora B激酶，一个有吸引力的化学治疗靶标，目前在临床试验中有几种Aurora抑制剂。这些抑制剂针对高度保守的ATP结合位点，因此仅显示有限的特异性，从而限制了其对研究和临床应用的适用性。与高度保守的催化位点相反，Aurora B与其激活支架之间的相互作用是这两种蛋白质所独有的，代表了潜在的，但没有开发的靶标。在此应用中，我们将利用实验室中开发的试剂和测定法，以筛选出新型的Aurora B活动的变构，以用作研究和临床应用的探针。构成该提案的特定目的的实验线将：1）开发高=基于流动仪的筛选，以识别破坏Aurora b/incenp Intrations的候选小分子； 2）采用化学生物学方法在体外和体内优化这些分子的功效。这些实验将在NM Inm-Inbre Chemical Biology＆Screen Collagorative Core（CBSC）和UNM分子库筛选中心进行，在该中心开发了高通量流式细胞仪，用于化学图书馆的生化和细胞基础筛选。从这些研究中，可以预料，不仅将开发新的试剂来研究细胞分裂，而且这些试剂可能会转化为临床领域，在这些临床领域中，这种临界结构的靶向代表了化学治疗干预的绝佳目标。