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）：蛋白激酶广泛参与人类疾病，特别是癌症，并在人类生物学中发挥重要作用。为了理解所谓的“磷酸化蛋白质组”，人们需要新的工具来解决在给定的信号转导网络中哪些特定的激酶是活性的（通常是磷酸化的）。几乎所有目前用于鉴定药物诱导的特定激酶的表达水平和磷酸化状态的蛋白质阵列技术都利用基于抗体的捕获方法。然而，抗体捕获剂是昂贵的，通常是不可扩展的，并且最近的报告强烈地表明，少于30%的可用抗体可以用于微阵列技术。为了提供一种可行的抗体替代品，该提案旨在系统地开发一类新的用于激酶的二价捕获剂（BCA），其将高亲和力小分子连接至噬菌体展示肽。BCA具有生产特异性、可扩展性和经济性的潜力。这些显著的特征使得我们的BCAs作为用于阵列技术的新型试剂具有吸引力，用于理解激酶磷酸化的调节，激酶磷酸化在人类疾病，特别是癌症中受到干扰的许多信号网络中起着核心作用。 公共卫生相关性：蛋白激酶位于信号转导级联的核心，当受到干扰时会导致人类疾病，如癌症。因此，在微阵列应用中识别用于捕获激酶的新类型的二价试剂在理解人类疾病的病理生理学方面具有直接效用，并且有助于开发新的诊断和治疗。