Kinase Binding Fluorescent Probes for Assaying Cellular Receptor Populations

用于测定细胞受体群的激酶结合荧光探针

• 批准号: 8738629
• 负责人: James Norbert Wilson
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738629
• 关键词: Address; Advanced Malignant Neoplasm; Antibodies; Basic Science; Binding; Biological Assay; Biological Markers; Biological Models; Cancer Biology; Cell Survival; Cells; Cellular Assay; Chemicals; Clinical; Complex; Dependency; Detection; Development; Diagnostic; Dissection; Drug Evaluation; Drug resistance; Dyes; EGFR gene; Environment; Epitopes; Equilibrium; Event; Family; Feasibility Studies; Feedback; Fingerprint; Fluorescence; Fluorescent Probes; Generations; Goals; Gold; Imatinib; Investigation; Knowledge; Life; Malignant Neoplasms; Measurement; Membrane; Modeling; Molecular; Molecular Probes; Monoclonal Antibodies; Nuclear; Oncogenic; Optical reporter; Optics; Pathway interactions; Performance; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Population; Preclinical Drug Evaluation; Predictive Value; Property; Protein Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Relative (related person); Reporting; Research; Resistance; Role; Sampling; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Specificity; Specimen; Specimen Handling; Spectrum Analysis; Staging; Staining method; Stains; Structure; Technology; Testing; Time; Translating; Treatment Protocols; Variant; analytical method; analytical tool; base; biophysical properties; cancer classification; cell growth regulation; cellular imaging; chemical reaction; chemical synthesis; chemotherapy; clinical Diagnosis; clinical application; clinically relevant; density; design; drug development; drug discovery; fluorophore; inhibitor/antagonist; kinase inhibitor; lapatinib; meetings; next generation; patient population; pharmacophore; prototype; public health relevance; receptor; resistance mechanism; response; small molecule; tool

DESCRIPTION (provided by applicant): Receptor tyrosine kinases are primary targets for small molecule and monoclonal antibody chemotherapies given their key role in intracellular signaling pathways, regulation of cell growth and cell survival. Immunohistochemical (IHC) analysis of receptor levels is an essential component for cancer classification and attempts to predict the treatment regimens, however, IHC has significant limitations in its predictive value due to the fact that the basic science of receptor signaling has moved well beyond using simple protein levels as an indicator. We now appreciate the importance of kinase activation states that are controlled by multiple factors that have been individually confirmed to be highly relevant for their oncogenic potential. Yet our ability to translate this knowledge into analytical readouts tha are robust and clinically useful is lagging far behind our understanding of signaling events. Our goal is to generate protein kinase specific molecular probes, which will enable detection, quantification and detailed analyses of cancer-relevant signaling pathways alongside dynamic, real time analysis of systemic cellular perturbations. To achieve this goal, we will utilize chemical synthesis to generate candidate probes, characterize their performance as reporters by optical spectroscopy, evaluate their pharmacological properties against relevant cancer signaling pathways and validate their performance against current "gold standard" analytical methods. Successful execution of this research plan will provide a set of probes that provide an optical "fingerprint" with far more informational content and predictive power while being robust in its application for clinical staging, individualized evaluation of drug response, drug development and cancer pathway dissection.

说明(申请人提供)：受体酪氨酸激酶是小分子和单抗化疗的主要靶点，因为它们在细胞内信号通路、调节细胞生长和细胞存活方面发挥关键作用。免疫组织化学(IHC)对受体水平的分析是癌症分类和预测治疗方案的重要组成部分，然而，由于受体信号转导的基础科学已经远远超出了将简单的蛋白质水平作为指标的事实，IHC在其预测价值方面有很大的局限性。我们现在认识到由多种因素控制的激酶激活状态的重要性，这些因素已被单独证实与其致癌潜力高度相关。然而，我们将这些知识转化为强大的、临床上有用的分析读数的能力远远落后于我们对信号事件的理解。我们的目标是产生蛋白激酶特异的分子探针，这将使癌症相关信号通路的检测、量化和详细分析以及对全身细胞扰动的动态、实时分析成为可能。为了实现这一目标，我们将利用化学合成来生成候选探针，通过光谱分析来表征它们的性能，针对相关的癌症信号通路评估它们的药理特性，并根据当前的“金标准”分析方法验证它们的性能。这项研究计划的成功执行将提供一套探针，提供具有更多信息内容和预测能力的光学“指纹”，同时在临床分期、药物反应的个性化评估、药物开发和癌症路径解剖方面的应用也很强大。