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Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics

药物结合位点静电的全激酶组光谱研究

基本信息

批准号：
8527807
负责人：
Nicholas Mark Levinson
金额：
$ 9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-13 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527807
关键词：
Address Affect Benchmarking Binding Binding Sites Biological Assay Cancer Etiology Cause of Death Cell Proliferation Chemical Structure Chemicals Chronic Myeloid Leukemia Clinic Comparative Study Complex Cytotoxic agent DNA Sequence Rearrangement Data Set Development Disease Drug Binding Site Drug Industry Effectiveness Electrostatics Environment Fluorescence Fluorescence Spectroscopy Fluorescent Probes Goals Growth Human Hydrogen Bonding Location Malignant Neoplasms Malignant neoplasm of lung Maps Measurement Measures Mentors Methods Molecular Target Mutate Mutation Pathology Patients Pharmaceutical Preparations Phase Phosphotransferases Physical Chemistry Physical environment Play Property Protein Family Protein Kinase Protein Kinase Inhibitors Proteins Radiation therapy Radiosurgery Reporting Research Role Series Signal Pathway Site Spectrum Analysis Structure Techniques Testing Time Translating Variant Water Work analog base cancer type chemical group design electric field experience inhibitor/antagonist insight kinase inhibitor member molecular dynamics physical property protein kinase inhibitor research study scaffold small molecule success tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Protein kinases play central roles in the signaling pathways that regulate the growth and proliferation of cells, and aberrant kinase activity contributes to the development of many cancers. Recent success in treating particular cancers with targeted protein kinases inhibitors, notably lung cancer and chronic myeloid leukemia, underscores the importance of these proteins in oncogenesis, and highlights the need for additional kinase inhibitors to treat other cancers. The development of new kinase inhibitors is challenging because the high sequence conservation of the kinase ATP-binding site, the major site targeted by these small molecules, makes it difficult to obtain compounds that are selective for particular kinases. The current study aims to address this problem through an entirely new experimental approach that utilizes advances in physical chemistry. In Aim 1, a new spectroscopic technique called vibrational Stark spectroscopy will be used to construct a map of the electrostatics of the ATP-binding site and how it varies across the ~500 members of this protein family. These measurements will be made using kinase inhibitors that possess vibrational probes of electric field, in which the probes report on the electrostatics they experience when bound in the ATP- binding site. Because these electrostatic maps relate to how the physical environment in the ATP- binding site appears from the perspective of the inhibitors, they will yield direct insight into how changes to the chemical structure of the inhibitors would affect the interaction with kinases. Differences uncovered between kinases in these measurements could be exploited to design more selective drugs. In Aim 2, this possibility will be quantified by performing large-scale binding assays in which the selectivity of panels of kinase inhibitors will be revealed and directly compared to the electrostatics measurements to reveal how electrostatic variation dictates selectivity. While selectivity profiling is commonplace in the pharmaceutical industry, the comparison with the electrostatic maps determined in Aim 1 will allow the physical basis of inhibitor selectivity to be determined for the first time, guidingthe way to the development of inhibitors with new selectivity profiles. In Aim 3 the characterization of the ATP-binding site will be completed by studying how this environment is affected by the dynamic rearrangements of protein groups and bound water molecules. The protein kinases now constitute a major group of pharmacological targets, and taken together this work will constitute the first comprehensive experimental study of how the physical properties of these proteins dictate their interaction with drug molecules.

描述（由申请人提供）：蛋白激酶在调节细胞生长和增殖的信号传导途径中发挥核心作用，异常激酶活性有助于许多癌症的发展。最近在用靶向蛋白激酶抑制剂治疗特定癌症，特别是肺癌和慢性髓性白血病方面的成功，强调了这些蛋白在肿瘤发生中的重要性，并强调了对其他激酶抑制剂治疗其他癌症的需求。新激酶抑制剂的开发是具有挑战性的，因为激酶ATP结合位点（这些小分子靶向的主要位点）的高序列保守性使得难以获得对特定激酶具有选择性的化合物。目前的研究旨在通过一种全新的实验方法来解决这个问题，该方法利用了物理化学的进步。在目标1中，一种称为振动斯塔克光谱的新光谱技术将用于构建ATP结合位点的静电图，以及它如何在该蛋白质家族的约500个成员中变化。这些测量将使用具有电场振动探针的激酶抑制剂进行，其中探针报告它们在ATP结合位点结合时所经历的静电。因为这些静电图谱与ATP结合位点中的物理环境如何从抑制剂的角度出现有关，所以它们将产生对抑制剂的化学结构的变化将如何影响与激酶的相互作用的直接洞察。在这些测量中发现的激酶之间的差异可以用来设计更具选择性的药物。在目标2中，将通过进行大规模结合测定来量化这种可能性，其中将揭示激酶抑制剂组的选择性，并直接与静电测量进行比较，以揭示静电变化如何决定选择性。虽然选择性分析很常见，在制药工业中，与目标1中确定的静电图的比较将首次确定抑制剂选择性的物理基础，为开发具有新选择性特征的抑制剂指明道路。在目标3的ATP结合位点的表征将完成研究如何影响这种环境的蛋白质组和结合水分子的动态重排。蛋白激酶现在构成了一组主要的药理学靶点，这项工作将构成第一个全面的实验研究，这些蛋白质的物理性质如何决定它们与药物分子的相互作用。