Kinase selective small molecule conjugates as antibody surrogates

作为抗体替代物的激酶选择性小分子缀合物

• 批准号: 7707065
• 负责人: INDRANEEL GHOSH
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707065
• 关键词: Active Sites; Address; Affinity; Antibodies; Architecture; Bacteriophages; Binding; Cells; Cleaved cell; Coupling; Cyclic AMP-Dependent Protein Kinases; Cyclic Peptides; Dasatinib; Development; Dimerization; Disease; Early Diagnosis; Epidermal Growth Factor Receptor; Family; Functional disorder; Gefitinib; Generations; Goals; Gold; Heart; Hot Spot; Human; Human Biology; In Vitro; Lead; Ligands; Link; Malignant Neoplasms; Measures; Methodology; Methods; Microarray Analysis; Monitor; PDGFRB gene; Pan Genus; Peptide Library; Peptide Phage Display Library; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Protein Array; Protein Kinase; Protein Kinase Inhibitors; Proteome; Reagent; Regulation; Reporting; Role; Signal Transduction; Signal Transduction Pathway; Staurosporine; Technology; Testing; Therapeutic; base; human disease; inhibitor/antagonist; kinase inhibitor; novel diagnostics; novel strategies; phosphatase inhibitor; protein kinase inhibitor; public health relevance; response; scale up; small molecule; tool

DESCRIPTION (provided by applicant): Protein kinases are widely implicated in human disease, especially in cancer, and play a fundamental role in human biology. In order to understand the so-called "phospho-proteome" one needs new tools to address which particular kinase(s) are active (usually phosphorylated) in a given signal transduction network. Almost all current protein-array technologies for identifying drug-induced expression levels and phosphorylation states of specific kinases utilize antibody based capture methods. However antibody capture agents are expensive, often not scalable, and recent reports strongly suggest that fewer than 30% of available antibodies can be utilized in microarray technologies. In order to provide a viable alternative to antibodies, this proposal seeks to systematically develop a new class of bivalent capture agents (BCAs) for kinases that link high-affinity small molecules to phage-displayed peptides. BCAs have the potential to be specific, scalable, and economical to produce. These salient features makes our BCAs attractive as a new class of reagents for use in array technology for understanding the regulation of kinase phosphorylation, which plays a central role in numerous signaling networks that are perturbed in human diseases, especially cancer. PUBLIC HEALTH RELEVANCE: Protein-kinases lay at the heart of signal transduction cascades, which when perturbed lead to human diseases such as cancer. Thus, the identification of new classes of bivalent reagents for capturing kinases in microarray applications has direct utility in understanding the pathophysiology of human diseases and aid in the development of novel diagnostics and therapeutics.

描述（由申请人提供）：蛋白激酶广泛与人类疾病有关，尤其是在癌症中，并在人类生物学中起着基本作用。为了理解所谓的“磷酸化 - 蛋白质”，需要新的工具来解决特定的激酶在给定的信号转导网络中活跃（通常是磷酸化的）。几乎所有当前的蛋白质阵列技术都用于鉴定药物诱导的表达水平和特定激酶的磷酸化状态，利用基于抗体的捕获方法。然而，抗体捕获剂的昂贵，通常不可扩展，最近的报道强烈表明，在微阵列技术中，只有不到30％的可用抗体。为了提供抗体的可行替代方法，该提案旨在系统地开发新的二价捕获剂（BCAS），用于将高亲和力小分子与噬菌体脱落的肽联系起来。 BCA具有特定，可扩展性和经济性的潜力。这些显着特征使我们的BCA作为一种新的试剂吸引了阵列技术，用于了解激酶磷酸化的调节，该试剂在许多信号网络中起着核心作用，这些信号网络在人类疾病（尤其是癌症）中受到干扰。 公共卫生相关性：蛋白质激酶位于信号转导级联的核心，当受到干扰会导致人类疾病（例如癌症）。因此，在微阵列应用中捕获激酶的新型二价试剂的鉴定具有直接的效用，可以理解人类疾病的病理生理学，并有助于开发新颖的诊断和治疗学。