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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 细胞分裂过程中染色体倍性的维持需要染色体分离和胞质分裂的精确协调，以便在所有复制的姐妹染色单体正确附着到有丝分裂纺锤体并启动后期之前不会发生分裂。被称为染色体过客复合物 (CPC) 的保守多亚基因子通过其在有丝分裂早期动丝和胞质分裂期间纺锤体中区的功能，在协调有丝分裂和胞质分裂中发挥核心作用。它在细胞分裂中的重要作用使得 CPC 的催化亚基 Aurora B 激酶成为一个有吸引力的化疗靶点，目前有几种 Aurora 抑制剂正在进行临床试验。这些抑制剂以高度保守的 ATP 结合位点为目标，因此仅表现出有限的特异性，从而限制了它们在研究和临床应用中的适用性。与高度保守的催化位点相反，Aurora B 与其激活支架 INCENP 之间的相互作用是这两种蛋白质所独有的，代表了潜在但尚未开发的干预靶点。在此应用中，我们将利用实验室开发的试剂和测定法来筛选 Aurora B 活性的新型变构干扰剂，用作研究和临床应用的探针。构成该提案具体目标的实验路线将： 1) 开发高通量、基于流式细胞术的筛选，以识别破坏 Aurora B/INCENP 相互作用的候选小分子； 2）应用化学生物学方法来优化这些分子在体外和体内的功效。这些实验将与 NM-INBre 化学生物学和筛选协作核心 (CBSC) 以及新墨西哥大学分子库筛选中心合作进行，该中心开发了高通量流式细胞术，用于基于生化和细胞的化学库筛选。从这些研究中，预计不仅会开发出用于细胞分裂研究的新型试剂，而且这些试剂将有可能转化为临床领域，其中针对这一关键结构的靶向代表了化疗干预的极好目标。