DEVELOPMENT OF HIGHLY SELECTIVE PROTEIN AND LIPID KINASE INHIBITORS

高选择性蛋白质和脂质激酶抑制剂的开发

• 批准号: 8363788
• 负责人: KEVAN M. SHOKAT
• 金额: $ 0.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363788
• 关键词: Binding; Chemicals; Coupled; Development; Funding; Goals; Grant; Human Genome; Lipids; Mass Spectrum Analysis; Mediating; National Center for Research Resources; Organic Chemistry; Phosphotransferases; Principal Investigator; Protein Kinase; Proteins; Publications; Research; Research Infrastructure; Resolution; Resources; Roentgen Rays; Sampling; Signal Pathway; Source; Structure; Transducers; United States National Institutes of Health; Work; cost; design; inhibitor/antagonist; interest; kinase inhibitor; small molecule; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Protein and lipid kinases are important transducers of cellular information. There are 500+ protein kinases and 30+ lipid kinases in the human genome. We are interested in developing chemical approaches for understanding and deciphering kinase mediated signaling pathways. The goal of this project is to develop highly selective small molecule protein and lipid kinase inhibitors. These small molecules are designed to fit in the ATP binding pocket of the kinases. We use synthetic organic chemistry coupled with structural biology (X-ray co-crystal structures) to develop these molecules. We typically use focused syntheses of five or fewer steps and make on the order of 20 candidate inhibitors per design. This work requires standard structural characterization of the intermediates and final products for publication or structural assignment purposes. Typically we need high resolution mass spectrometry of the small molecules. They are often highly structurally related, allowing for parameters to be optimized and used for a number of samples at once.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 蛋白质和脂质激酶是细胞信息的重要转换器。 人类基因组中有500多种蛋白激酶和30多种脂质激酶。 我们有兴趣开发化学方法来理解和破译激酶介导的信号通路。 该项目的目标是开发高选择性的小分子蛋白和脂质激酶抑制剂。 这些小分子被设计成适合激酶的 ATP 结合袋。 我们利用合成有机化学与结构生物学（X 射线共晶结构）相结合来开发这些分子。 我们通常使用五个或更少步骤的集中合成，并在每个设计中制作大约 20 个候选抑制剂。 这项工作需要中间体和最终产品的标准结构表征，以用于出版或结构分配的目的。 通常我们需要对小分子进行高分辨率质谱分析。 它们通常在结构上高度相关，允许优化参数并同时用于多个样本。