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
基本信息
- 批准号:8167576
- 负责人:
- 金额:$ 10.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:AnaphaseBinding SitesBiochemicalBiologicalBiological AssayBiologyCatalytic DomainCell divisionCellsChemicalsChromosome SegregationClinicalClinical TrialsCollaborationsComplexComputer Retrieval of Information on Scientific Projects DatabaseCytokinesisDevelopmentFlow CytometryFundingGrantIn VitroInstitutionInterventionLaboratoriesMaintenanceMitosisMitotic spindleMolecular BankPhosphotransferasesPlayPloidiesProteinsReagentResearchResearch PersonnelResourcesRoleScreening procedureSignal TransductionSister ChromatidSourceSpecificityStructureTranslatingUnited States National Institutes of HealthWitaurora B kinasebaseclinical applicationin vivoinhibitor/antagonistinner centromere proteinnovelresearch studyscaffoldsmall moleculesmall molecule libraries
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
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.
这个子项目是许多研究子项目中利用
资源由NIH/NCRR资助的中心拨款提供。子项目和
调查员(PI)可能从NIH的另一个来源获得了主要资金,
并因此可以在其他清晰的条目中表示。列出的机构是
该中心不一定是调查人员的机构。
在细胞分裂过程中维持染色体倍性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连接到有丝分裂纺锤体并启动后期之前不会发生分裂。染色体乘客复合体(CPC)是一种保守的多亚基因子,它通过在有丝分裂早期的动粒中心和胞质分裂的纺锤体中部发挥作用,在协调有丝分裂和胞质分裂过程中发挥核心作用。它在细胞分裂中的重要作用使CPC的催化亚单位Aurora B Kinase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结合位点为靶点,因此只显示有限的特异性,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个蛋白质所独有的,是一个潜在的但尚未开发的干预靶点。在这项应用中,我们将利用实验室开发的试剂和分析方法来筛选Aurora B活性的新型变构干扰物,用作研究和临床应用的探针。形成这项提议的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,以确定干扰Aurora B/INCENP相互作用的候选小分子;以及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化学生物学和筛选合作核心(CBSC)和UNM分子图书馆筛选中心合作进行,在那里已经开发了高通量流式细胞术,用于基于生化和细胞的化学图书馆筛选。从这些研究中,预计不仅将开发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,在临床领域,靶向这一关键结构是化疗干预的良好靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Charles Bradley Shuster其他文献
Charles Bradley Shuster的其他文献
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{{ truncateString('Charles Bradley Shuster', 18)}}的其他基金
Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
- 批准号:
10617385 - 财政年份:2022
- 资助金额:
$ 10.85万 - 项目类别:
Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
- 批准号:
10409136 - 财政年份:2022
- 资助金额:
$ 10.85万 - 项目类别:
Parameters that determine cell fate during mitotic arrest
有丝分裂停滞期间决定细胞命运的参数
- 批准号:
10797794 - 财政年份:2022
- 资助金额:
$ 10.85万 - 项目类别:
Spindle orientation along the developmental axes in echinoderm embryos
棘皮动物胚胎沿发育轴的纺锤体方向
- 批准号:
8733008 - 财政年份:2014
- 资助金额:
$ 10.85万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 10.85万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
8292148 - 财政年份:2009
- 资助金额:
$ 10.85万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
7904769 - 财政年份:2009
- 资助金额:
$ 10.85万 - 项目类别:
CHARACTERIZATION OF MOB1 DYNAMICS IN LIVING CELLS
活细胞中 MOB1 动力学的表征
- 批准号:
7960229 - 财政年份:2009
- 资助金额:
$ 10.85万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
8070024 - 财政年份:2009
- 资助金额:
$ 10.85万 - 项目类别:
Mob1 Localization and Function During Mitosis
Mob1 在有丝分裂期间的定位和功能
- 批准号:
7628920 - 财政年份:2009
- 资助金额:
$ 10.85万 - 项目类别:
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