Covalent Fluorescent Probes for Cancer Cell Detection

用于癌细胞检测的共价荧光探针

• 批准号: 8065765
• 负责人: WEI ZHANG
• 金额: $ 6.1万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065765
• 关键词: Affinity Chromatography; BODIPY; Benzodiazepines; Biological Markers; Biotin; Boston; Cancer Biology; Cancer Center; Cancer cell line; Cell physiology; Cells; Chromosomal Rearrangement; Collaborations; Cysteine; Dana-Farber Cancer Institute; Detection; Development; Epidermal Growth Factor Receptor; Equilibrium; Event; Family; Fibroblast Growth Factor Receptors; Fluorescence; Fluorescent Probes; Gene Amplification; Genes; Goals; Gray unit of radiation dose; Imagery; Institution; Label; Libraries; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Methods; Microscopy; Persons; Phosphotransferases; Point Mutation; Population; Protein Kinase; Relative (related person); Research Personnel; Screening procedure; Site; Staining method; Stains; Training; Yang; abstracting; base; biological systems; cancer cell; career; career development; cellular engineering; covalent bond; fluorescence imaging; imaging probe; inhibitor/antagonist; kinase inhibitor; medical schools; member; novel; scaffold; sensor; skills; small molecule; tool

Abstract: Fluorescence imaging is a powerful tool that permits visualization of specific cell states within a population; however, existing methods for fluorescence labeling are not experimentally accessible for many biological systems. Furthermore, fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging. The overall goal of this project is to create fluorescent small molecule ATP-site directed probes that can selectively label particular kinases and serve as imaging probes of normal versus pathological cell state. Protein kinases are in many ways ideal targets for the development of selective small molecule imaging probes for use in cancer biology. This is because protein kinases are involved in most cellular processes and changes in their localization, accessibility, and abundance are associated with changes in cellular state. Protein kinases have been used as biomarkers in cancer biology because the loss of endogenous kinase regulatory mechanisms by point mutations, gene deletions, gene amplifications, and chromosomal rearrangements has been well-established as crucial events in many cancers. The specific aims of this project are to: 1) Synthesize fluorescently-tagged kinase inhibitors capable of forming covalent bonds with ATP-site cysteine residues; 2) Use microscopy-based screening ofthe compounds prepared in Aim 1 to identify compounds that are selective-probes of normal and pathological cellular states and 3) Identify the intracellular target(s) of active compounds identified in Aim 2. This proposed is the extension of an ongoing collaboration between Drs. Nathanael Gray (Dana Farber Cancer Institute), Priscilla Yang (Harvard Medical School) and Wei Zhang (UMass Boston). All three are also members of the Dana Farber/Harvard Cancer Center. One of the strong points of this proposal is that each Co-Pl is responsible for one of the three Specific Aims allowing the project to be benefited by the balanced skills and expertise that each person and their subsequent institution brings to the partnership. Because all three investigators are eariy in their careers, Drs. Gray, Yang and Zhang will benefit from career development activities and mentors who are intemal and extemal. Additionally, the Training Core will significantiy contribute to this project.

摘要：荧光成像是一种强大的工具，可以可视化群体内特定的细胞状态；然而，现有的荧光标记方法在实验上对许多生物系统是不可行的。此外，相对于现有的荧光成像方法，荧光小分子细胞状态传感器可能提供一个有价值的替代方案，具有显著的优势。的总体目标