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: 8167576
• 负责人: Charles Bradley Shuster
• 金额: $ 10.85万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8167576
• 关键词: Anaphase; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Catalytic Domain; Cell division; Cells; Chemicals; Chromosome Segregation; Clinical; Clinical Trials; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytokinesis; Development; Flow Cytometry; Funding; Grant; In Vitro; Institution; Intervention; Laboratories; Maintenance; Mitosis; Mitotic spindle; Molecular Bank; Phosphotransferases; Play; Ploidies; Proteins; Reagent; Research; Research Personnel; 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; 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. 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.

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